Tricyclic indole compounds having an affinity against serotonin receptors

ABSTRACT

Having an affinity against serotonine receptors, compound (I) shown below is useful as a therapeutic agent against various kinds of diseases of central nervous systems.  
                 
 
(wherein R 1  is hydrogen; R 2  is hydrogen or lower alkyl; R 3  is hydrogen, —COOR 12  and so on; R 4  is hydrogen, lower alkyl and so on, or R 3  and R 4  taken together may form ═O or ═S; R 5  is hydrogen, or R 3  and R 5  taken together may form a bond; R 6  is hydrogen, —COOR 24  and so on; R 7  is hydrogen, halogen, lower alkyl and so on; R 8  is hydrogen, lower alkyl, cycloalkyl and so on; R 9 , R 10  and R 11  are each independently hydrogen, halogen, lower alkyl and so on)

TECHNICAL FIELD

The present invention is related to tricyclic indole compounds. Having an affinity against serotonin receptors, the present compounds are useful as medicines, for example, a therapeutic agent for diseases of central nervous system thereof and useful as synthetic intermediates thereof.

BACKGROUND ART

Serotonin (5-hydroxytryptamine) is one of amines, which exists in living body, and has a lot of physiological activities. For example, serotonin is located in granule cell of intestinal basal and promotes the movement of the intestinal tract. And also, on an occasion of bleeding, serotonin is released from platelets into blood and concerned with hemostasis by contracting blood capillary. Apart from this, serotonin works as a neurotransmitter in brain and takes part in modulating mental action, limit of pain, body-temperature and sleep-awakening cycle thereof, through serotonin receptors [Physiol. Rev. 72(1992) 165-229].

It has been reported that serotonin receptors are classified mainly to seven families and by including their subtypes, at least 14 kinds of receptors have been identified until now. Each receptor is reported to be concerned with various kinds of physiological functions and diseases [Pharmacol. Rev. 46(1994) 157-203]. Displaying to have agonistic or antagonistic activities, an agent having a binding affinity against serotonin receptors, is expected to be a therapeutic or prophylactic medicament. [Pharmacol.Rev. 43(1991) 509-525]

Among them, 5-HT_(5A), 5-HT_(5B), 5-HT₆ and 5-HT₇ are receptors which have been recently identified and cloned [FEBS Lett. 355(1994) 242-6, FEBS Lett. 333(1993) 25-31, J. Neurochem. 66(1996) 47-56, Neuron, 11(1993) 449-458] and there is few report about the selective agonist and antagonist. Each of these receptors has already been known to be located mainly in central nervous system. For example, it has been reported that 5-HT_(5A) and 5-HT_(5B) receptors are located in hippocampus and cerebral cortex, which are profoundly concerned with learning and memory [FEBS Lett. 35-5 (1994) 242-6, FEBS Lett. 333 (1993) 25-31], 5-HT₆ receptor is located in corpus striatum, which is concerned with motor function [J. Neurochem. 66 (1996) 47-56], and 5-HT₇ receptor is located in suprachiasmatic nucleus, which is concerned with mammalian biological clock [Neuron, 11(1993) 449-458]. Therefore, there is a possibility for the selective agonist or antagonist against the receptor to be a therapeutic agent for dementia, Parkinson's disease, psychosis or diseases concerning circannual rhythm thereof. Selective agonists and antagonists against serotonin receptors other than 5-HT_(5A), 5-HT_(5B), 5-HT₆ and 5-HT₇ receptors have already been launched as therapeutic agents for various kinds of diseases.

Furthermore, indole derivatives having an affinity against serotonin receptors have been disclosed; for example, compounds of a 4-membered ring type are disclosed in WO 96/32944, WO 95/28403, EP 0738513 and so on and compounds of a 3-membered ring type are disclosed in GB 2341549, WO 98/00400, JP 99-189585A and so on. However, these indole derivatives do not contain oxygen as an ring element. Moreover, naturally occurring heterocyclyl type of indole derivatives are described in WO 00/59909.

Under the situations mentioned above, development of novel compounds having an affinity against serotonin receptors and medicines containing them have been desired.

DISCLOSURE OF INVENTION

The present inventors have intensively studied to find that tricyclic indole compounds have an affinity against serotonin receptors, and accomplished the present invention shown below.

(1) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof of the formula

wherein

-   R¹ is hydrogen; -   R² is hydrogen or lower alkyl; -   R³ is hydrogen, —COOR² (R¹² is hydrogen or ester residue) or —CN; -   R⁴ is hydrogen, lower alkyl, —COOR¹³ (R¹³ is hydrogen or ester     residue), —CONR¹⁴R¹⁵ (R¹⁴ and R¹⁵ are each independently hydrogen,     lower alkyl, cycloalkyl, lower alkenyl, optionally substituted     aralkyl, optionally substituted aryl, or optionally substituted     heteroaryl, or R¹⁴ and R¹⁶ taken together with a neighboring     nitrogen atom may form 5- to 7-membered heterocycle), —CN, —NO₂,     —NR¹⁶R¹⁷ (R¹⁶ and R¹⁷ are each independently hydrogen, —CN,     optionally substituted lower alkyl, cycloalkyl,     cycloalkyl(lower)alkyl, lower alkenyl, optionally substituted     aralkyl, optionally substituted aryl, optionally substituted     heteroaryl, or optionally substituted amino, or R¹⁶ and R¹⁷ taken     together with a neighboring nitrogen atom may form optionally     substituted 5- to 7-membered heterocycle), —NR¹⁸COR¹⁹ (R¹⁸ and R¹⁹     are each independently hydrogen, optionally substituted lower alkyl,     cycloalkyl, cycloalkyl lower alkyl, lower alkenyl, optionally     substituted aralkyl, optionally substituted aryl, or optionally     substituted heteroaryl), —NR²⁰COOR²¹ (R²⁰ is hydrogen, lower alkyl,     cycloalkyl, cycloalkyl(lower)alkyl, lower alkenyl, optionally     substituted aralkyl, optionally substituted aryl, or optionally     substituted heteroaryl; R²¹ is ester residue), —NR²²SO₂R²³ (R²² is     hydrogen, lower alkyl, cycloalkyl, cycloalkyl(lower)alkyl, lower     alkenyl, optionally substituted aralkyl, optionally substituted     aryl, or optionally substituted heteroaryl; R²³ is lower alkyl,     cycloalkyl, lower alkenyl, optionally substituted aralkyl,     optionally substituted aryl, optionally substituted heteroaryl, or     lower alkylamino), —OH, lower alkoxy, —SH, or lower alkylthio, or R³     and R⁴ taken together may form ═O, ═S, or lower alkylenedioxy; -   R⁵ is hydrogen, or R³ and R⁵ taken together may form a bond; -   R⁶ is hydrogen, —COOR²⁴ (R²⁴ is hydrogen or ester residue), —CN, or     —CH₂NR²⁵R²⁶ (R²⁵ and R²⁶ are each independently hydrogen, lower     alkyl, cycloalkyl, or lower alkenyl) -   R⁷ is hydrogen, halogen, —CN, optionally substituted lower alkyl,     cycloalkyl, cycloalkyl(lower)alkyl, optionally substituted lower     alkenyl, optionally substituted aralkyl, optionally substituted     aryl, optionally substituted heteroaryl, optionally substituted     amino, —COOR³⁴ (R³⁴ is hydrogen or ester residue), —COR³⁵ (R³⁵ is     hydrogen, lower alkyl, cycloalkyl, lower alkenyl, optionally     substituted aralkyl, optionally substituted amino, optionally     substituted aryl, or optionally substituted heteroaryl) or —CHNOH; -   R⁸ is hydrogen, optionally substituted lower alkyl, cycloalkyl,     cycloalkyl(lower)alkyl, lower alkenyl, optionally substituted     aralkyl, optionally substituted aryl, optionally substituted     heteroaryl, —COR²⁷ (R²⁷ is hydrogen, lower alkyl, cycloalkyl, lower     alkenyl, optionally substituted aralkyl, optionally substituted     aryl, or optionally substituted heteroaryl, —COOR²⁸ (R²⁸ is ester     residue), —SO₂R²⁹ (R²⁹ is lower alkyl, cycloalkyl, optionally     substituted lower alkenyl, optionally substituted aralkyl,     optionally substituted aryl, optionally substituted heteroaryl) or     tri-lower alkylsilyl; -   R⁹, R¹⁰ and R¹¹ are each independently hydrogen, halogen, optionally     substituted lower alkyl, cycloalkyl, cycloalkyl(lower)alkyl,     optionally substituted lower alkenyl, lower alkoxy, —OH, —CN, —SR³⁰     (R³⁰ is hydrogen or lower alkyl), —CONH₂, —CHO, —CHNOH, —COOR³¹ (R³¹     is hydrogen or ester residue), —NR³²R³³ (R³² and R³³ are each     independently hydrogen or lower alkyl), optionally substituted aryl,     or optionally substituted heteroaryl.

(2) A compound, prodrug, pharmaceutically acceptable salt, or solvate thereof according to the above 1, wherein R² is hydrogen.

(3) A compound, prodrug, pharmaceutically acceptable salt, or solvate thereof according to the above 1, wherein R³ is hydrogen.

(4) A compound, prodrug, pharmaceutically acceptable salt, or solvate thereof according to the above 1, wherein R⁵ is hydrogen.

(5) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 1, wherein R³ and R⁵ taken together may form a bond.

(6) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 1, wherein R³ and R⁴ taken together may form ═O, ═S or lower alkylenedioxy.

(7) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 1, wherein R⁴ represents —COOR¹³ (R¹³ is hydrogen or lower alkyl), —NR¹⁶R¹⁷ (R¹⁶ and R¹⁷ are each independently hydrogen, optionally substituted lower alkyl, cycloalkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted amino, or R¹⁶ and R¹⁷ taken together may form an optionally substituted 5 to 7 membered heterocyclyl ring with the neighboring nitrogen atom), —NR¹⁸COR¹⁹ (R¹⁸ and R¹⁹ are each independently hydrogen, optionally substituted lower alkyl or optionally substituted aralkyl), —NR²⁰COOR²¹ (R²⁰ is hydrogen, or lower alkyl; R²¹ is an ester moiety), —NR²²SO₂R²³ (R²² is hydrogen; R²³ is lower alkyl or lower alkylamino), —OH, or lower alkoxy.

(8) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 1, wherein R⁴ is —COOR³ (R¹³ is hydrogen or methyl), —NR¹⁶R¹⁷ (R¹⁶ is hydrogen or lower alkyl, R¹⁷ is hydrogen, optionally substituted lower alkyl, cycloalkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted amino, optionally substituted amino or R¹⁶ and R¹⁷ are taken together may form an optionally substituted 5 to 7 membered heterocyclyl ring with the neighboring nitrogen atom), —NR¹⁸COR¹⁹ (R¹⁸ is hydrogen, R¹⁹ is hydrogen, optionally substituted lower alkyl or optionally substituted aralkyl), —NR²⁰COOR²¹ (R²⁰ is hydrogen or methyl; R²¹ is methyl), —NR²²SO₂R²³ (R²² is hydrogen; R²³ is methyl or methylamino), —OH, or lower alkoxy.

(9) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 1, wherein R⁴ is —NH₂, —NHCH₃ or —N(CH₃)₂.

(10) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 1, wherein R⁶ is hydrogen, COOCH₃, COOCH₂CH₃, CN, or CH₂NH₂.

(11) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 1, wherein R⁶ is hydrogen.

(12) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 1, wherein R⁷ is hydrogen, lower alkyl, halogen, phenyl, —COOR³⁴ (R³⁴ is mentioned before), —CHO or —CHNOH.

(13) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 1, wherein R⁷ is hydrogen, methyl, ethyl, halogen or phenyl.

(14) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 1, wherein R⁸ is hydrogen, optionally substituted lower alkyl, —COR²⁷ (R²⁷ is hydrogen, lower alkyl, cycloalkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, or optionally substituted heteroaryl), —COOR²⁸ (R² is ester moiety), or —SO₂R²⁹ (R²⁹ is lower alkyl, cycloalkyl, optionally substituted lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted heteroaryl), or tri-lower alkylsilyl.

(15) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 1, wherein R⁸ is hydrogen or —SO₂R²⁹ (R²⁰ is mentioned before)

(16) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 1, wherein all of R⁹, R¹⁰ and R¹¹ are hydrogen.

(17) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 1, wherein R² is hydrogen; R³ and R⁵ are both hydrogen or taken together may form a bond.

(18) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 16 and 17, wherein R⁶ is hydrogen, COOCH₃, COOCH₂CH₃, CN, or CH₂NH₂; R⁷ is hydrogen, lower alkyl, halogen or phenyl; R⁸ is hydrogen, lower alkyl, COPh, or SO₂Ph (Ph represents phenyl).

(19) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 1, wherein R⁹ is hydrogen or halogen.

(20) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 1, wherein R⁹ is hydrogen.

(21) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 1, wherein R¹⁰ is hydrogen.

(22) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 1, wherein R¹¹ is hydrogen, halogen, lower alkyl, optionally substituted lower alkenyl, —CN, —SR³⁰(R³⁰ is hydrogen or lower alkyl), —CONH₂, —CHO, —CHNOH, —N³²R³³ (R³² and R³³ are each independently hydrogen or lower alkyl) or aryl.

(23) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 1, wherein R¹¹ is hydrogen, halogen, methyl, —CN, or —CONH₂.

(24) A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to the above 1, wherein R¹, R², R³, R⁵, R⁶, R⁹, and R¹⁰ is hydrogen; R⁴ is NH₂, —NHCH₃, or —N(CH₃)₂; R⁷ is hydrogen, halogen, lower alkyl, or phenyl; R⁸ is hydrogen or —SO₂R²⁹ (R²⁹ is mentioned before); R¹¹ is hydrogen, halogen, lower alkyl, —CN, or —CONH₂.

(25) A pharmaceutical composition containing a compound, prodrug, pharmaceutically acceptable salt or solvate thereof according to any one of the above 1-24.

(26) A therapeutic or prophylactic medicament against the serotonin receptors mediated diseases, comprising a compound, prodrug, pharmaceutically acceptable salt or solvate thereof according to any one of the above 1-24.

(27) A therapeutic or prophylactic medicament according to the above 26, wherein the serotonine receptor is a 5-HT₆ receptor.

(28) A therapeutic or prophylactic medicament according to the above 26, wherein the disease is that of central nervous system.

(29) A therapeutic or prophylactic medicament according to the above 28, wherein the disease of the central nervous system is schizophrenia, Alzheimer's disease, Parkinson's disease, depression, anxiety, pain or migraine.

(30) A method for treating or preventing the serotonin receptors mediated diseases, which comprises administrating to said mammal an effective amount of a compound, prodrug, pharmaceutically acceptable salt or solvate thereof according to any one of the above 1-24.

(31) Use of a compound, prodrug, pharmaceutically acceptable salt or solvate thereof according to any one of the above 1-24, in order to prepare a therapeutic or prophylactic medicament for the serotonin receptors mediated diseases.

BEST MODE FOR CARRYING OUT THE INVENTION

Each group of compound (I) is explained below. Each term used herein is defined to have meanings described below in either case of a single or a joint use with other terms, unless otherwise noted.

“Halogen” refers to F, Cl, Br, I.

“Lower alkyl” includes a straight-chain and branched-chain C₁-C₆ alkyl group and refers to methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, i-pentyl, neo-pentyl, tert-pentyl, n-hexyl and the like, preferably a C₁-C₄ alkyl group and more preferably a C₁-C₃ alkyl group, such as methyl, ethyl, n-propyl, and i-propyl.

“Lower alkenyl” includes a straight-chain and branched-chain C₂-C₆ alkenyl group and refers to vinyl, allyl, 1-propenyl, 2-butenyl, 3-butenyl, 1-pentenyl, prenyl, 2-hexenyl and the like, preferably vinyl, allyl or prenyl and the like.

“Lower alkoxy” includes oxy groups binding to an above mentioned lower alkyl group, and refers to methoxyl, ethoxyl, n-propoxyl, i-propoxyl, tert-butoxy, pentyloxy, hexyloxy and the like, preferably a C₁-C₄ alkoxyl group and more preferably a C₁-C₃ alkoxyl group such as methoxyl, ethoxyl, n-propoxyl, and i-propoxyl.

“Cycloalkyl” includes C₃-C₈ cycloalkyl and refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like, preferably a C₅-C₇ cycloalkyl group such as cyclopentyl, cyclohexyl, and cycloheptyl.

“Cycloalkyl(lower)alkyl” means an above mentioned lower alkyl group bound with an above mentioned cycloalkyl group and refers to cyclopropylmethyl, 2-cyclopropyl ethyl and the like.

“Lower alkylthio” includes a thio group bound with an above mentioned lower alkyl group and refers to methylthio, ethylthio, i-propylthio, tert-butylthio, pentylthio, hexylthio and the like, preferably methylthio.

“Aryl” used herein means a single or fused aromatic hydrocarbon ring system and refers to phenyl, naphthyl (such as α-naphthyl, and β-naphthyl), anthryl, indenyl, phenanthryl and the like, preferably phenyl or naphthyl.

“Lower alkylenedioxy” includes a straight-chain and branched-chain C₁-C₆ alkylendioxy group, preferably methylenedioxy, ethylenedioxy, or trimethylenedioxy, more preferably ethylenedioxy.

“Aralkyl” used herein means a lower alkyl group bound with an above mentioned aryl group, refers to benzyl, phenethyl, phenylpropyl (such as 3-phenylpropyl), naphthylmethyl (such as α-naphthylmethyl), anthrylmethyl such as 9-anthrylmethyl and the like.

“Heteroaryl” used herein means a single or polycyclic aromatic ring system in which the ring contains the same or different heteroatom selected from the group of O, S and N.

The single aromatric ring system includes a 5- to 7-membered ring moiety in which the heterocycle contains 1 to 4 heteroatoms and refers to furyl, thienyl, tetrazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, thiadiazolyl, pyridinyl, oxazinyl, triazinyl and the like, preferably 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl.

Polycyclic aromatic ring system includes a di- or tri-heterocyclic moiety in which the heterocycle contains 1 to 5 heteroatoms and refers to benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzoxazoly, benzothiazolyl, benzotriazolyl and the like.

5- to 7-Membered heterocycle formed by “R¹⁴ and R¹⁵” or “R¹⁶ and R¹⁷” taken together with the neighboring nitrogen, refers to pyrrolydine, piperidine, azepine, piperazine, morpholine and the like, preferably pyrrolydine, piperazine or morpholine.

Substituents on the aryl, heteroaryl or heterocyclyl ring refer to halogen, hydroxy, amino, carboxy, cyano, nitro, carbamoyl, sulfamoyl, lower alkyl (such as methyl or ethyl), halo-lower alkyl (such as —CCF₃), lower alkyl-carbamoyl (such as methylcarbamoyl), lower alkyl-sulfamoyl (such as methylsulfamoyl), lower alkoxy (such as methoxyl), lower alkoxycarbonyl (such as ethoxylcarbonyl), a 5- to 7-membered heterocyclyl group such as isoxazolyl and the like, preferably halogen, methyl, methoxyl, trihalo-methyl such as trifluoromethyl preferably 1 to 3 of these groups can be substituted.

“Ester” residue refers to lower alkyl, optionally substituted aralkyl and the like, preferably, methyl, ethyl, n-propyl, i-propyl, tert-butyl, benzyl and the like.

“Lower alkyl” or “lower alkenyl” can be optionally substituted, in which a substituent refers to hydroxy, halogen, amino and optionally mono- or di-lower alkyl substituted carbamoyl (such as carbamoyl, and dimethylcarbamoyl), phenyl, phenylamino, cyclohexylamino, lower alkoxy, lower alkoxycarbonyl such as methoxylcarbonyl and the like.

An optional substitutent on amino groups refers to lower alkyl, lower alkoxycarbonyl and the like.

Preferred examples are shown below.

-   (1) both of R¹ and R⁵ are hydrogen. -   (2) all of R¹, R³, and R⁵ are hydrogen. -   (3) R¹ is hydrogen; R³ and R⁴ are taken together may form a bond. -   (4) R¹ is hydrogen; R³ and R⁴ are taken together may form ═O or ═S.

Other preferred examples are shown in following tables. TABLE 1 R² R³ R⁴ R⁶ H H H H methyl COOR¹² methyl COOR²⁴ ethyl CN ethyl CN n-propyl n-propyl CH₂NR²⁵R²⁶ i-propyl i-propyl COOR¹³ CONR¹⁴R¹⁵ CN NO₂ NR¹⁶R¹⁷ NR¹⁸COR¹⁹ NR²⁰COOR²¹ NR²²SO₂R²³ OH methoxyl ethoxyl n-propoxyl i-propoxyl SH methyl thio ethyl thio n-propylthio i-propylthio —O(CH₂)₂O—

TABLE 2 R⁷ R⁸ R⁹, R¹⁰, R¹¹ H H H F methyl F Cl ethyl Cl Br n-propyl Br I i-propyl I methyl cyclopropylmethyl methyl ethyl cyclopentyl ethyl n-propyl cyclohexyl n-propyl i-propyl cycloheptyl i-propyl cyclopropylmethyl vinyl cyclopropylmethyl cyclopentyl allyl cyclopentyl cyclohexyl prenyl cyclohexyl cycloheptyl benzyl cycloheptyl vinyl phenethyl vinyl allyl phenyl allyl prenyl 2-furyl prenyl benzyl 3-furyl OH phenethyl 2-pyridinyl methoxyl phenyl 3-pyridinyl ethoxyl 2-furyl 4-pyridinyl n-propoxyl 3-furyl 2-pyrrolyl i-propoxyl 2-pyridinyl 3-pyrrolyl CN 3-pyridinyl 2-thienyl CHO 4-pyridinyl 3-thienyl SCH₃ 2-pyrrolyl COR²⁷ CH═N—OH 3-pyrrolyl COOR²⁸ CONH₂ 2-thienyl SO₂R²⁹ phenyl 3-thienyl Si(iPr)₃ CH═CHCO₂CH₃ CN

TABLE 3 R¹², R¹³ R¹⁴, R¹⁶ R¹⁵, R¹⁷ H H H methyl methyl methyl ethyl ethyl ethyl n-propyl n-propyl n-propyl i-propyl i-propyl i-propyl t-butyl cyclopropyl methyl cyclopropylmethyl benzyl cyclopentyl cyclopentyl cyclohexyl cyclohexyl cycloheptyl cycloheptyl allyl allyl prenyl prenyl benzyl benzyl phenethyl phenethyl phenyl phenyl 2-furyl 2-furyl 3-furyl 3-furyl 2-pyridinyl 2-pyridinyl 3-pyridinyl 3-pyridinyl 4-pyridinyl 4-pyridinyl 2-pyrrolyl 2-pyrrolyl 3-pyrrolyl 3-pyrrolyl 2-thienyl 2-thienyl 3-thienyl NHBoc cyclopropyl CH₂CF₃ —CH₂CH₂CH₂CH₂— —CH₂CH₂CH₂CH₂CH₂— —CH₂CH₂CH₂CH₂CH₂CH₂— —CH═CH—CH═CH— —CH₂CH₂NHCH₂CH₂— —CH₂CH₂NCH₃CH₂CH₂— —CH₂CH₂OCH₂CH₂—

TABLE 4 R²¹ R¹⁸, R¹⁹, R²⁰, R²² R²³ methyl H methyl ethyl methyl ethyl n-propyl ethyl n-propyl i-propyl n-propyl i-propyl t-butyl i-propyl cyclopropylmethyl benzyl cyclopropylmethyl cyclopentyl cyclopentyl cyclohexyl cyclohexyl cycloheptyl cycloheptyl vinyl allyl allyl prenyl prenyl benzyl benzyl phenethyl phenethyl phenyl phenyl 2-furyl 2-furyl 3-furyl 3-furyl 2-pyridinyl 2-pyridinyl 3-pyridinyl 3-pyridinyl 4-pyridinyl 4-pyridinyl 2-pyrrolyl 2-pyrrolyl 3-pyrrolyl 3-pyrrolyl 2-thienyl 2-thienyl 3-thienyl 3-thienyl CH₂N(CH₃)₂ NHCH₃ CF₃ CH₂NH-cyclohexyl

TABLE 5 R²⁴ R²⁵, R²⁶ H H methyl methyl ethyl ethyl n-propyl n-propyl i-propyl i-propyl t-butyl cyclopropylethyl benzyl cyclopentyl cyclohexyl cycloheptyl vinyl allyl prenyl

TABLE 6 R²⁷ R²⁸ R²⁹ H methyl methyl methyl ethyl ethyl ethyl n-propyl n-propyl n-propyl i-propyl i-propyl i-propyl t-butyl cyclopropylmethyl cyclopropylmethyl benzyl cyclopentyl cyclopentyl cyclohexyl cyclohexyl cycloheptyl cycloheptyl vinyl vinyl allyl allyl prenyl prenyl benzyl benzyl phenethyl phenethyl phenyl phenyl 2-furyl 2-furyl 3-furyl 3-furyl 2-pyridinyl 2-pyridinyl 3-pyridinyl 3-pyridinyl 4-pyridinyl 4-pyridinyl 2-pyrrolyl 2-pyrrolyl 3-pyrrolyl 3-pyrrolyl 2-thienyl 2-thienyl 3-thienyl 3-thienyl α-naphthyl mono or diCl-phenyl CF₃-phenyl Br-phenyl mono or dimethoxy phenyl Br-diF-phenyl phenyl vinyl mono or diF-phenyl Cl-thienyl isoxyazolylthienyl

The following cases are more preferable.

R² is more preferably hydrogen or methyl and particularly preferable is hydrogen.

R³ and R⁶ are more preferably both hydrogen or taken together may form a bond and particularly preferable is hydrogen.

R⁴ is preferably —COOR¹⁸ (R¹⁸ is hydrogen or lower alkyl), —NR¹⁶R¹⁷ (R¹⁶ and R¹⁷ is each independently hydrogen, optionally substituted lower alkyl, cycloalkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted amino, or R¹⁶ and R¹⁷ taken together may form optionally substituted 5- to 7-membered heterocyclyl with the neighboring nitrogen atom), —NR¹⁸COR¹⁹ (R¹⁸ and R¹⁹ are each independently hydrogen, optionally substituted lower alkyl or optionally substituted aralkyl), —NR²⁰COOR²¹ (R²⁰ is hydrogen, or lower alkyl; R²¹ is ester residue), —NR²²SO₂R²³ (R²² is hydrogen; R²³ is lower alkyl or lower alkylamino), —OH, lower alkoxy. R⁴ is preferably —COOR¹³(R¹³ is hydrogen or methyl), —NR¹⁶R¹⁷(R¹⁶ is hydrogen or lower alkyl, R¹⁷ is hydrogen, optionally substituted lower alkyl, cycloalkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted amino, or R¹⁶ and R¹⁷ taken together may form optionally substituted 5- to 7-membered heterocyclyl with the neighboring nitrogen atom), —NR¹⁸COR¹⁹ (R¹⁸ is hydrogen, R¹⁹ is hydrogen, optionally substituted lower alkyl or optionally substituted aralkyl), —NR²⁰COOR²¹ (R²⁰ is hydrogen or methyl; R²¹ is methyl), —NR²²SO₂R²³(R²² is hydrogen; R²³ is methyl or methylamino), —OH, lower alkoxy. R⁴ is preferably —NH₂, —NHCH₃, or —N(CH₃)₂.

R⁶ is more preferably hydrogen, COOMe (Me is methyl), COOEt (Et is ethyl), CN, or CH₂NH₂, more preferably hydrogen.

R⁷ is preferably hydrogen, lower alkyl, halogen, phenyl, —COOR³⁴ (R³⁴ is hydrogen or ester residue), —CHO or —CHNOH, more preferably hydrogen, methyl, ethyl, halogen, or phenyl.

R⁸ is more preferably hydrogen, optionally substituted lower alkyl, —COR²⁷ (R²⁷ is hydrogen, lower alkyl, cycloalkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, or optionally substituted heteroaryl), —COOR²⁸ (R²⁸ is ester residue), or —SO₂R²⁹ (R²⁹ is lower alkyl, cycloalkyl, optionally substituted lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted heteroaryl), or tri-lower alkyl silyl, more preferably hydrogen or —SO₂R²⁹ (R²⁹ is lower alkyl, cycloalkyl, optionally substituted lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted heteroaryl). R²⁹ is more preferably mono- or di-Cl-phenyl, CF₃-phenyl, Br-phenyl, mono- or di-methoxyphenyl, phenylvinyl, mono- or di-F-phenyl, Cl-thienyl, naphthyl.

R⁹ is preferably hydrogen or halogen, more preferably hydrogen.

R¹⁰ is preferably hydrogen.

R¹¹ is preferably hydrogen, halogen; lower alkyl, optionally substituted lower alkenyl, —CN, —SR³⁰ (R³⁰ is hydrogen or lower alkyl), —CONH₂, —CHO, —CHNOH, —NR³²R³³ (R³² and R³³ is each independently hydrogen or lower alkyl) or aryl, more preferably hydrogen, halogen, methyl, —CN, or —CONH₂.

In a preferred compound among compound (I), R¹, R², R³, R⁵, R⁶, R⁹, and R¹⁰ are hydrogen; R⁴ is —NH₂, —NHCH₃, or —N(CH₃)₂; R⁷ is hydrogen, halogen, lower alkyl or phenyl; R⁸ is hydrogen or —SO₂R²⁹ (R²⁹ is mentioned before); R¹¹ is hydrogen, halogen, lower alkyl, —CN, or —CONH₂.

A produg of compound (I) is a derivative of compound (I), which has a chemically or metabolically decomposible group and can get back to a pharmaceutically active present invention compound by the solvolysis or under physiological conditions in vivo. Methods of selection and production of a suitable prodrug derivative has been, disclosed, for example in Design of Prodrugs, Elsevier, Amsterdam 1985. Having a carboxylic acid group, the original acidic compound can be exemplified to be reacted with an appropriate alcohol derivative to give the ester derivative or reacted with a suitable amino derivative to give the amide derivative as the prodrug. Having a hydroxyl group, the hydroxyl compound for example can be exemplified to be reacted with appropriate acid halides or acid anhydrides to give the acyloxy derivative as the prodrug. Having an amino group, the amino compound can be exemplified to be reacted with a suitable acid halide or acid anhydride to give the amide compound as the prodrug.

A pharmaceutically acceptable salt of compound (I) or the prodrug refers to those salts, which are obtained by reacting with inorganic acids, inorganic bases, ammonia, organic bases, inorganic acids, organic acids, basic amino acids, ionic halogen and the like, or the internal salt. The inorganic base refers to alkaline metals (Na, K and the like), alkaline-earth metal (Ca, Mg and the like). Organic base refers to trimethylamine, triethylamine, corrine, procaine, ethanolamine and the like. The inorganic acid refers to hydrochloric acid, hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, and the like. The organic acid refers to p-toluenesulfonic acid, methanesulfonic acid, formic acid, trifluoroacetic acid, maleic acid and the like. Basic amino acid refers to lysine, arginine, ornithine, histidine and the like.

A solvate of compound (I) refers to the hydrate or alcholate and the like. The racemic or the optically active compound (I) and the like are all included in the present invention.

Compound (I) can be prepared from indole derivatives and the like as starting material which are well known or can be obtained easily by the synthesis. General method of preparation is shown below.

(Method 1 of Preparation)

(The 1st Process)

Compound (III) can be obtained by reacting indole derivative (II) with vinyl compound (IV) (X¹ is H) in the presence of a base. This reaction can be accomplished fundamentally according to the Baylis-Hillman vinyl alkylation condition. The reaction temperature can be exemplified to be −20-50° C. and the solvent can be illustrated to be tetrahydrofuran (THF), dioxane, dichloromethane, chloroform and the like. Excess vinyl compound can be used as the solvent, also. As the base, 1,4-diazabicyclo[2,2,2]octane (DABCO), tri-n-butylphosphine and the like can be exemplified. The reaction time is ordinarily: several hours to several days.

The preparation of compound (III) is also possible by reacting the acetylene compound R²C≡CR⁴ (V) with the vinyl compound (III) (X¹ is Al(i-Bu)₂), obtained from compound R² C≡CR⁴ (V) and diisopropylaluminumhydride (DIBAL). The reaction to the vinyl aluminum compound can be carried out according to a similar manner of well-known methods (for example: the method is disclosed in J. Org. Chem., 1988, 53, 1037.). The reaction temperature is exemplified to be ordinarily −100 to 50° C. and the solvent is tetrahydrofuran (THF), dioxane, dichloromethane and the like. The reaction temperature is normally several hours to tens of hours.

(The 2nd Process)

Compound (III) is cyclized under a Mitsunobu reaction condition to give compound (I-1) of the present invention. The Mitsunobu reaction can be carried out according to the well-known ordinary method (for example, a method disclosed in Synthesis, 1981,1). The reaction temperature used are exemplified to be −50-50° C. and the solvent used are exemplified to be tetrahydrofuran (THF), dioxane, benzene, toluene, dichloromethane and the like, respectively. Among reagents, 1,1′-(azodicarbonyl)-diethyl ester, 1,1′-(azodicarbonyl)-diisopropyl ester, 1,1′-(azodicarbonyl)-dipiperidine and the like are used in this reaction as diazocarboxylic acid ester derivatives. Further, triphenylphosphine, tri-n-butylphosphine and the like can be exemplified as phosphine derivatives. The reaction time is ordinarily several hours to tens of hours.

Furthermore, compound (I-1) can be obtained by cyclizing compound (III) in the presence of base. Moreover, in order to increase the yield of the reaction, it is preferable that the secondary hydrokyl group is first changed to the appropriate removable group such as acetoxyl group and the like and then the cyclization reaction is carried out in the presence of base. The reaction temperature can be exemplified to be 0-100° C. and the solvents can be exemplified to be tetrahydrofuran (THF), dioxane, toluene, acetone, acetonitrile, and the like, respectively. Potassium carbonate, NaH, pyridine, triethylamine and the like can be exemplified as the base used. The reaction time is ordinarily several hours to tens of hours.

Furthermore, it is possible in the 1st process to convert to compound (I-1) through the only one step by reacting compound (II) with compound (IV) (X¹ is H) at relatively high temperature (20-50° C.).

Furthermore, it is possible to convert to compound (I-1) through the only one step by reacting compound (II) and compound (IV) (X¹ is —PO(OMe)₂) under the presence of base. The reaction temperature is ordinarily −20-50° C. Tetrahydrofuran (THF), dioxane, toluene, dichloromethane and the like can be exemplified as the solvent. Potassium tert-butoxyde and the like can be exemplified as the base. The reaction time is ordinarily several hour to tens of hours.

According to the above reaction, preferably a compound, in which R⁴ in compound (I-1) is electron-withdrawing group, is obtained. As the electron-withdrawing group, ester group, carboxylic acid group, cyano group, amide group, aldehyde group, nitro group and the like are exemplified.

Compound (I-1) is a compound (I) in the present invention, where R¹ and R⁶ are both hydrogen and R³ and R⁵ taken together may form a bond. Compound (I-1) can be derived to other compounds of the present invention by chemical modifications. For example, compound a (I-1), where R⁴ is carboxylic acid, can be transferred to the various kinds of ester and amide compounds by converting to the acid chloride with thionyl chloride and the like or to the acid anhydride with ethyl chloroacetate and the like under the existence of base such as triethylamine, followed by reacting with the various kinds of alcohol or amino derivatives. Furthermore, compound (I-1) can also be transferred to the various kinds of ester and amide compounds by using appropriate condensing agents such as dicyclohexylxarbodiimide, carbonyldiimidazole and the like. Further, if the reaction is carried out according to Curtius reaction or Hofmann reaction, compound in which R⁴ is carbamate can be obtained. Moreover, compound in which R⁴ is hydroxy (or R³ and R⁴ taken together may form ═O) can be prepared by the hydrolysis of the compound in which R⁴ is carbamate. Furthermore, by reduction catalytically or with sodium borotriacetoxyhydride under the presence of appropriate base, compound, in which R³ and R⁴ taken together may form ═O, can be transferred to compounds in which R⁴ is various kind of N-alkyl groups.

(The 3rd Process))

Compound (I-2) of the present invention can be obtained by the reduction of compound (I-1). Compound (I-2) is a compound (I) of the present invention, where all of R¹, R³, R⁵ and R⁶ are hydrogen. The reduction reaction is carried out preferably by a catalytic reduction (Pd/C, H2) thereof. By further chemical modifications of compound (I-2), another compound of the present invention can be obtained. For example, in the case where R⁴ is primary or secondary amino group, compound (I-2) can be converted to the various kinds of N-sulfonyl or N-acyl compounds by reacting with various kinds of sulfonyl chloride or acyl chloride in the presence of base such as triethylamine and the like. Furthermore, compound (I-2) can be transferred to various kinds of N-alkyl compounds by reacting with various kinds of alkyl halide under the presence of base such as triethylamine and the like or by reduction catalytically or with sodium triacetoxyborohydride in the presence of various kinds of aldehydes or ketones. (Method 2 of Preparation)

Compound (I-3) of the present invention can be obtained by cyclization of indole derivative (IV) (X² is a removing group such as lower alkoxy and the like) preferably under the presence of base. Compound (I-3) is a compound in which R³ and R⁵ taken together may form a bond and R⁴ is a hydroxy group in compound (I).

As the solvent, ether, tetrahydrofuran (THF), dioxane and the like are exemplified. NaH, sodium metal, potassium tert-butoxyde lithium bis(trimethylsilyl)amide and the like are exemplified as the base. The reaction time is ordinarily several hours to tens hours. By this reaction, a preferred compound is obtained, in which R⁶ is an electron-withdrawing group such as carboxylic acid group, ester group, cyano group.

Moreover, R¹ and R² are preferably hydrogen in the above preparations Furthermore, if necessary, the group can be protected before the reaction and de-protected after the reaction by the well-known method. For example, R⁸ in the intermediate is preferably an amino protecting group such as Boc. Compounds obtained by the above method of preparation of the present invention can be transferred to another compound of this invention by further chemical modifications of well-known reaction such as oxidation, reduction, protection, deprotection, rearrangement reaction, halogenation, hydroxylation, alkylation, alkylthiolation, demethylation, O-alkylation, O-acylation, N-alkylation, N-alkenylation, N-acylation, N-cyanation, N-sulfonylation, coupling reaction using transition metals and the like.

Having an affinity against various kinds of serotonin receptors, compound (I) has functions as the agonist or antagonist. Therefore, compound (I) is useful as a therapeutic or prophylactic medicine to various serotonin receptor mediated diseases, such as diseases of central nervous systems such as sleep-awakening lesion, circadian rhythm lesion, anxiously mental disorder, schizophrenia, cerebral stroke, dementia, pain, Alzheimer's disease, Parkinson's disease, depression, anxiety, megrim and the like. A specifically preferable compound (I) described above has an affinity against 5HT_(1A), 5HT₆, 5HT₇ among serotonin receptors and more preferably has a high selective affinity against 5HT₆. Increase of the selectivity against 5HT₆ can be achieved preferably by introducing various kinds of substituents to R⁷ and R¹¹ and so on. Then, compound (I) is useful to the selectively 5HT₆ receptor mediated diseases among the diseases of central nervous system (for example, schizophrenia, Alzheimer's disease, Parkinson's disease, depression, anxiety, migraine and the like).

Compound (I) can be administrated orally or parenterally to mammals including human. Granule, tabula, capsules, injections, suppositorium and the like can be exemplified as an admirable dosage form. In pharmaceutical manufacturing, if necessary, following various additive agents can be used, for example remedium constituens (lactose, mannitol, crystalline cellulose, starch and the like), disintegrators (carmellose, hydroxypropylmethyl cellulose, polyvinylpolypyrrolidone and the like), binding agent (methylcellose, hydroxypropylcellose, cellose, poloyvinylalcohol and the like), lubricant (Magnesium stearate, talc and the like), stabilizing agent, coloring agent, coating material. Dosage varies depending on the examinee's age, body weight, condition of diseases and dosage forms and so on. Generally, dosage is ca. 0.001 mg to 1 g/day to an adult in oral or parenteral administration. Number of administration time is one to several times/day.

Examples of this invention are described below without limiting the present invention thereto. “Ex” in the Scheme of reaction corresponds to the number of Example, e.g. “Ex 1” means compound (1) obtained by the procedure cited in Example 1.

(Abbreviated Words)

Me=methyl; Et=ethyl; tBu=t-butyl; nPr=n-propyl; Ph=phenyl; Ts=p-toluene sulfonyl; Bn=benzyl; Ms=methanesulfonyl

EXAMPLE 1 OF REFERENCE

4-Hydroxyindole-3-carbaldehyde (1-1) (R⁷=R¹¹=H)

Phosphorous oxychloride 7.35 ml was added dropwise to dry dimethylformamide 15 ml under cooling in ice-methanol bath and the mixture was stirred for 15 min. Then, a solution of the 4-hydroxyindole 5.0 g in dry dimethylformamide 10 ml was added dropwise to the mixture under cooling in ice and the mixture was stirred for 2 h at room temperature. Water was added under cooling in ice to the mixture, which was made alkaline with a 30% aqueous sodium hydroxide solution and was stirred for 15 min. Then, the mixture was acidified to pH 4 with 5N—HCl and the precipitate was collected by filtration, washed with water and dried to give the titled compound 4.99 g as crude crystalline materials. Yield 82%. Crude crystalline materials are recrystallized from methanol to give yellow crystals m.p. 190-193° C.

¹H-NMR(DMSO-d₆): 6.54 (1H, dd, J=8.1, 0.9 Hz), 6.95 (1H, dd, J=8.1, 0.9 Hz), 7.13 (1H, t, J=8.1 Hz), 8.37 (1H, s), 9.64 (1H, s), 10.54 (1H, br s), 12.35 (1H, br s). Following compounds were obtained, according to the similar treatment. Compd No R⁷ R¹¹ m.p. (° C.) ¹H-NMR(DMSO-d₆) 1-2 Ph H 239-247 6.57(1H, dd, J=8.1, 0.9Hz), 6.95(1H, dd, J=8.1, (dec.) 0.9Hz), 7.17(1H, t, J=8.1Hz), 7.61-7.82(5H, m), 9.56(1H, s), 11.05(1H, s), 12.67(1H, br s) 1-3 Me Me 269-272 2.16(3H, s), 2.66(3H, s), 6.72(1H, d, J=8.1Hz), (dec.) 6.93(1H, d, J=8.1Hz), 9.64(1H, br s), 11.05(1H, s), 12.14(1H, br s)

EXAMPLE 2 OF REFERENCE

3-Formyl-4-hydroxyindole-1-carboxylic acid tert-butyl ester (2-1) (R⁷=R¹¹=H)

A mixture of the 3-formyl-4-hydroxyindole (1-1) 323 mg, di-tert-butyldicarbonate 458 mg, dimethylaminopyridine 12.5 mg and acetonitrile 25 ml was stirred under cooling in ice for 3 h. The solvent was removed under reduced pressure and the residue obtained was recrystallized from acetone-isopropyl ether to give the titled 10 compound as pale yellow crystals, m.p. 159-161° C. (dec.), 389 mg. Yield 74%.

¹H-NMR(CDCl₃): 1.71 (9H, s), 6.84 (1H, dd, J=8.1, 0.9 Hz), 7.31 (1H, t, J=8.1 Hz), 7.61 (1H, dd, J=8.1, 0.9 Hz), 8.25 (1H, s), 9.76 (1H, d, J=0.6 Hz), 10.13 (1H, s). Following compounds were obtained, according to the similar treatment. Compd No R⁷ R¹¹ m.p. (° C.) ¹H-NMR(CDCl₃) 2-2 Ph H 154-155 1.26(9H, s), 6.86(1H, dd, J=8.4, 0.9Hz), 7.33(1H, (dec.) t, J=8.4Hz), 7.43-7.53(5H, m), 7.66(1H, dd, J=8.4, 0.9Hz), 9.36(1H, s), 10.64(1H, s) 2-3 Me Me 177-179 1.71(9H, s), 2.30(3H, s), 2.88(3H, s), 7.09(1H, d, J=8.4Hz), (dec.) 7.39(1H, d, J=8.4Hz), 9.90(1H, br s), 10.92(1H, s)

EXAMPLE 3 OF REFERENCE

5-Bromo-3-formyl-4-hydroxyindole-1-carboxylic acid tert-butyl ester (2-4)

Compound (2-1) 26.1 g was suspended in dry tetrahydrofuran 260 ml and chloroform 260 ml. Pyridinium bromide perbromide 33.6 g was added to the suspension under cooling in ice and the mixture was stirred at room temperature for 4.5 h. An aqueous sodium hydrogen carbonate 16.77 g solution was added to the reaction mixtures, which were extracted with chloroform. The extracts were washed with water, dried over anhydrous magnesium sulfate, concentrated up to the deposition of crystals and diluted with isopropanol. Appeared crystals were collected by filtration to give the titled compound as yellow crystals. 29.1 g. Yield 86%. m.p. 239-242° C. (dec.)

¹H-NMR(CDCl₃): 1.71 (9H, s), 7.52 (2H, s), 8.24 (1H, s), 9.75 (1H, s), 10.91 (1H, br s). (Scheme of Reactions, Examples 1-5)

EXAMPLE 1

7H-6-Oxa-2-azabenzo[c,d]azulene-2,8-dicarboxylic acid 2-tert-butyl ester 8-methyl ester (3-1) (R⁷=R¹¹=H)

(Method 11)

60% Sodium hydride 23.0 mg was suspended in dry tetrahydrofuran 4 ml. Compound (2-1) 123 mg and trimethyl-2-phosphonoacrylate 116 μl were added with cooling in ice under nitrogen atmosphere and the mixture was stirred for 19 h. Water was added to the mixture with cooling in ice and the mixture was extracted with ethyl acetate. The extracts were washed with water, dried over anhydrous magnesium sulfate and chromatographed on silica gel 25 g in ethyl acetate: hexane (1:10) to give the titled compound (3-1) as colorless crystals, 46 mg. Yield 30%.

¹H-NMR(CDCl₃): 1.69 (9H, s), 3.84 (3H, s), 5.06 (2H, s), 6.85 (1H, dd, J=7.5, 0.6 Hz), 7.24 (1H, t, J 7.5 Hz), 7.74 (1H, s), 7.77 (1H, d, J=7.5 Hz), 8.00 (1H, s).

(Method 2)

Compound (2-1) 140 mg, 1,4-diazabicyclo[2.2.2]octane 70 mg was suspended in methyl acrylate 1.4 ml and the suspension was stirred at room temperature for 4 days. Ethyl acetate was added to the reaction mixtures and the insoluble materials were filtered off. The filtrate was concentrated under reduced pressure and chromatographed on silica gel 25 g in ethyl acetate hexane (1:10) to give titled compound (3-1) as colorless crystals 59 mg. Yield 34%.

(Method 3)

(a) 4-Hydroxy-3-(1-hydroxy-2-methoxycarbonylallyl)indole-1-carboxylic acid tert-butyl ester (4-1) (R⁷=R¹¹=H)

Compound (2-1) 140 mg and 1,4-diazabicyclo[2.2.2]octane 70 mg were suspended in methyl acrylate 1.4 ml with cooling in ice and the suspension was stirred at 4° C. for 24 h. The reaction mixtures was chromatographed on silica gel in ethyl acetate hexane several times to give the titled compound (4-1) as a colorless oil 178 mg.

Yield 96%.

¹H-NMR (CDCl₃): 1.66 (9H, s), 3.86 (3H, s), 5.05 (1H, br s), 5.63 (1H, s), 5.81 (1H, s), 6.39 (1H, s), 6.78 (1H, dd, J=8.1, 0.9 Hz), 7.24 (1H, t, J=8.1 Hz), 7.31 (1H, s), 7.67 (1H, d, J=8.1 Hz), 9.10 (1H, br s).

Following compounds were obtained, according to the similar treatment. Compd No R⁷ R¹¹ m.p. (° C.) ¹H-NMR(CDCl₃) 4-2 Ph H 121-122 1.21(9H, s), 3.82(3H, s), 5.01(1H, br s), 5.51(2H, s), 6.35(1H, s), 6.81(1H, dd, J=7.8, 0.6Hz), 7.28(1H, t, J=8.4Hz), 7.38-7.40(5H, m), 7.83(1H, dd, J=8.4, 0.6Hz), 9.14(1H, s) 4-3 Me Me 155-156.5 1.68(9H, s), 2.29(3H, s), 2.48(3H, s), 3.87(3H, s), 5.14(1H, br s), 5.37(1H, s), 5.96(1H, s), 6.30(1H, s), 7.05(1H, d, J=8.4Hz), 7.56(1H, d, J=8.4Hz), 9.27(1H, s) 4-4 H Br Colorless 1.66(9H, s), 3.85(3H, s), 5.13(1H, d, J=5.4Hz), 5.62(1H, oil s), 5.82(1H, d, J=5.4Hz), 6.39(1H, s), 7.32(1H, s), 7.44(1H, d, J=8.7Hz), 7.57(1H, d, J=8.7Hz), 9.59(1H, br s) (b) 7H-6-Oxa-2-azabenzo[c,d]azulene-2,8-dicarboxylic acid 2-tert-butyl ester 8-methyl ester (3-1)

Triethylamine 20.1 mg, 1,1′-(azodicarbonyl)-dipiperidine 42.0 mg and triphenylphosphine 43.9 mg were dissolved in dry tetrahydrofuran 1 ml. Compound (4-1) 37 mg was added to the solution with cooling in ice under nitrogen. The mixture was stirred at room temperature for 17 h. Water was added with cooling in ice and the reaction mixture was extracted with ethyl acetate. The extracts were washed with water, dried over anhydrous magnesium sulfate and chromatographed on silica gel 15 g in ethyl acetate hexane (1:3) to give titled compound (3-1) as colorless crystals, 17 mg. Yield 48%.

(C) 7H-6-Oxa-2-azabenzo[c,d]azulene-2,8-dicarboxylic acid 2-tert-butyl ester 8-methyl ester (3-1) (R⁷=R¹¹=H)

Acetic anhydride 0.38 ml was added to a solution of compound (4-1) 1.32 g in pyridine 13.1 ml with cooling in ice under nitrogen. The mixture was stirred at that temperature for 1 h The solvent was removed by distillation under reduced pressure and the residue obtained was chromatographed on silica gel 60 g in ethyl acetate: hexane (1:3) to give a yellow oil 860 mg. The oily compound 747 mg was dissolved in dioxane 0.7 ml and potassium carbonate 530.5 mg was added. The mixture was stirred at 80° C. for 6 h, filtered through cerite and chromatographed on silica gel 40 g in ethyl acetate:hexane (1:10) to give the titled compound (3-1) as colorless crystals, 501 mg. Yield 40%, m.p. 124-126 C (recrystallized from isopropanol) Following compounds were obtained, according to the similar treatment. Compd No R⁷ R¹¹ m.p. (° C.) ¹H-NMR(CDCl₃) 3-2 Ph H 151-152 1.26(9H, s), 3.75(3H, s), 5.08(2H, s), 6.87(1H, dd, J=8.1, 0.9Hz), 7.27(1H, t, J=8.1Hz), 7.35-7.49(5H, m), 7.65(1H, s), 7.87(1H, dd, J=8.1, 0.9Hz) 3-3 Me Me 112-114 1.69(9H, s), 2.31(3H, s), 2.70(3H, s), 3.84(3H, s), 5.03(2H, s), 7.04(1H, d, J=8.4Hz), 7.61(1H, d, J=8.4Hz), 8.07(1H, s) 3-4 H Br 160-161 1.68(9H, s), 3.84(3H, s), 5.14(2H, s), 7.46(1H, d, J=9.0Hz), 7.68(1H, d, J=9.0Hz), 7.74(1H, s), 7.99(1H, s) (Method 4) 4-Hydroxy-3-(1-hydroxy-2-methoxycarbonylallyl)-2,5-dimethylindole-1-carboxylic acid tert-butyl ester (4-3) (R⁷=R¹¹=H)

Diisobutylaluminumhydride (0.9 mol/l hexane solution) 50 ml was added to a mixture of hexamethylphosphorous triamide (8.96) g and dry tetrahydrofuran 80 ml with cooling in ice under a nitrogen atmosphere. The mixture was stirred for 30 min. Methyl propiorate 3.78 g was added and he mixture was stirred for 1 h with cooling in ice. Compound (2-3) 4.36 g was added to the reaction mixture, which was stirred for 10 min and then at room temperature for 2 h. 1N—HCl 50 ml was added with cooling in ice and the mixture was extracted with ethyl acetate. The extracts were washed with 1N—HCl, water, brine and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel 130 g in ethyl acetate:hexane (1:4) to give colorless crystals which were recrystallized from ethyl acetate hexane to give the titled compound, 4.47 g. Yield 80%, m.p. 155-156.5° C.

EXAMPLE 2

2,7-Dihydro-6-oxa-2-azabenzo[c,d]azulene-8-carboxylic acid (5-1) (R⁷=R¹¹=H)

The above obtained compound (3-1) 1.01 g was dissolved in tetrahydrofuran 15 ml and 1N sodium hydroxide 15 ml was added to the solution. The mixture was stirred for 1 h. Methanol 7.5 ml was added. The mixture was stirred at 50° C. for 3 h, acidified with 2N—HCl 7.5 ml to weakly acidic with cooling in ice and extracted with ether. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a yellow solid, which was recrystallized from methanol to give the titled compound (5-1), m.p. 230° C. (dec.) as yellow crystals, 450 mg. From the mother liquor, the second crop 134 mg was obtained by crystallization from isopropanol. Yield 88%.

¹H-NMR (CD₃OD): 4.98 (2H, s), 6.60 (1H, m), 7.02-7.08 (2H, m), 7.55 (1H, s), 8.19 (1H, s).

Following compounds were obtained, according to the similar treatment. Compd No R⁷ R¹¹ m.p. (° C.) ¹H-NMR(DMSO-d₆) 5-2 Ph H 218-220 4.98(2H, s), 6.59-6.60(1H, m), 7.06-7.13(2H, m), (dec.) 7.51-7.68(5H, m), 8.05(1H, s), 12.27(1H, br s) 5-3 Me Me 203-206 2.20(3H, s), 2.48(3H, s), 4.87(2H, s), 6.84-6.89(2H), (dec.) 8.03(1H, s), 11.69(1H, s), 12.03(1H, br s) 5-4 H Br 210-215 4.97(2H, s), 7.07(1H, d, J=8.4Hz), 7.27(1H, d, J=8.7Hz), (dec.) 7.83(1H, s), 8.09(1H, s), 12.07(1H, s)

EXAMPLE 3

(2,7-Dihydro-6-oxa-2-azabenzo[c,d]azulen-8-yl)carbamic acid tert-butyl ester (6-1) (R⁷=H).

Triethylamine 0.38 ml and chloroethyl carbonate 0.26 ml were added to a solution of the compound obtained by Ex. 2 (5-1) 530 mg in dry tetrahydrofuran 5 ml with cooling in ice-methanol bath and the mixture was stirred for 30 min. Then an aqueous solution of sodium azide 320 mg/water 2 ml was added dropwise and the mixture was stirred for 4 h with cooling in ice-methanol bath. Water was added and the reaction mixture was extracted with ethyl acetate. The extracts were washed with brine and dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a yellow solid. The residue obtained was suspended in toluene 20 ml and heated under reflux at 125° C. for 20 min and concentrated under reduced pressure. The residue obtained was again suspended in t-butanol 20 ml, heated at 100° C. for 2.5 h and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel 50 g in ethyl acetate:hexane (1:3) to give brown crystals, which was recrystallized from ether-petrolether to give the titled compound (6-1) m.p. 125-130° C. (dec.) as pale brown crystals, 436 mg. Yield 62%.

¹H-NMR (CDCl₃): 1.50 (9H, s), 4.76 (2H, s), 6.01 (1H, br s), 6.64 (1H, dd, J=7.2, 1.2 Hz), 6.98-7.12 (3H, m), 8.17 (1H, br s).

Following compounds were obtained, according to the similar treatment. Compd m.p. No R⁷ (° C.) ¹H-NMR(CDCl₃) 6-2 Ph 201-202 1.49(9H, s), 4.90(2H, br s), 6.11(1H, br s), (dec.) 6.67(1H, m), 6.88-7.41(5H, m), 7.49(1H, m), 7.59(1H, d, J=8.4Hz), 8.24(1H, br s)

EXAMPLE 4

(2,7,8,9-Tetrahydro-6-oxa-2-azabenzo[c,d]azulen-8-yl)carbamic acid tert-butyl ester (7-1) (R⁷=H)

5% Pd/C 100 mg was added to a solution of the compound obtained in Ex. 3 460 mg in methanol 10 ml. The mixture was stirred in a hydrogen atmosphere for 1.5 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue obtained was chromatographed on silica gel in ethyl acetate hexane (1:3) to give the titled compound (7-1) as a reddish oil, 390 mg. Yield 84%. ¹H-NMR (CDCl₃): 1.41 (9H, s), 2.98-3.10 (1H, m), 3.26-3.38 (1H, m), 4.23 (1H, d, J=12.0 Hz), 4.27-4.40 (1H, m), 4.48-4.58 (1H, m), 6.67 (1H, dd, J=7.2, 0.9 Hz), 6.98 (1H, br s), 7.02 (1H, dd, J=7.2, 0.9 Hz), 7.09 (1H, t, J=7.2 Hz), 8.13 (1H, br s).

Following compounds were obtained, according to the similar treatment. Compd m.p. No R⁷ (° C.) ¹H-NMR(CDCl₃) 7-2 Ph 188-189 1.38(9H, s), 3.18(1H, m), 3.43(1H, m), 4.29(1H, d, J=12.0Hz), 4.39(1H, m), 4.56(1H, m), 5.08(1H, br s), 6.70(1H, m), 7.04(1H, m), 7.11(1H, t, J=7.8Hz), 7.34-7.55(5H, m), 8.28(1H, br s)

EXAMPLE 5

2,7,8,9-Tetrahydro-6-oxa-2-azabenzo[c,d]azulen-8-ylamine (8-1)

The compound obtained in Ex 4 (7-1) 262 mg was dissolved in ethyl acetate 3 ml. A solution of 4 N HCl/ethyl acetate 2 ml was added to the solution with cooling in ice and the mixture was stirred at room temperature for 3 h. Furthermore, 4N-HCl/ethyl acetate 1 ml was added and the mixture was stirred at room temperature for 1 h. After the volatile materials were remove by distillation under reduced pressure up to the half volume, the mixture was diluted with ethyl acetate 10 ml. An aqueous saturated sodium hydrogen solution carbonate was added to alkaline with cooling in ice. The mixture was extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a brown oily residue, which was chromatographed on aluminum oxide 40 g in methanol:chloroform (3:97) to give the titled compound (8-1) as brown crystals, 144 mg. Yield 84%.

Further, this oil was recrystallized from isopropanol to give the titled compound (8-1) as gray crystals, 60 mg. m.p. 172-173° C.

¹H-NMR (CD₃OD): 2.84-2.93 (1H, ddd, J=15.6, 8.7, 1.5 Hz), 3.17-3.25 (1H, m), 3.36-3.43 (1H, m), 4.12-4.25 (2H, m), 6.43-6.50 (1H, m), 6.89-7.00 (3H, m).

Following compounds were obtained, according to the similar treatment. Compd m.p. No R⁷ (° C.) ¹H-NMR(CDCl₃) 8-2 Ph 189-191 3.09(1H, dd, J=15.6, 8.1Hz), 3.29(1H, dd, J=15.6, 3.6Hz), 3.59(1H, m), 4.27-4.36(2H, m), 6.67(1H, m), 7.01(1H, m), 7.10(1H, t, J=8.1Hz), 7.34-7.59(5H, m), 8.25(1H, br s)

Scheme of reactions, Examples 6-10 are shown in below.

EXAMPLE 6

8-Hydroxy-2,7-dihydro-6-oxa-2-azabenzo[c,d]azulene-9-carbonitrile (10)

Compound (9) 200 mg was dissolved in dry tetrahydrofuran 10 ml. 60% Sodium hydride 72 mg was added to the solution with cooling in ice and the mixture was stirred at room temperature for 2.5 h. After excess sodium hydride was decomposed with ethanol with cooling in ice, 2 N-HCl 1.5 ml was added. The mixture was extracted with ether. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel 4 g in ether to give an eluent 187 mg which was again chromatographed on silica gel 5 g in ether to give the titled compound (10) as reddish orange crystals, 132 mg. Yield 79.5%.

¹H-NMR (CDCl₃): 4.80 (2H, s), 6.52 (1H, dd, J=7.5, 0.9 Hz), 6.99 (1H, t, J=7.5 Hz), 7.06 (1H, dd, J 7.5, 0.9 Hz), 7.24 (1H, d, J=2.7 Hz), 11.07 (1H, s), 11.39 (1H, s).

EXAMPLE 7

(1) 3-Ethoxycarbonylmethyl-1H-indol-4-yloxy)acetic acid ethyl ester (11)

Compound (9) 1.49 g was dissolved in 95% ethanol 45 ml. Concentrated sulfuric acid 4.5 ml was added to the solution. The mixture was heated under reflux for 40 h. After the solvent was removed under reduced pressure, ice-water was added to the mixture, which was extracted with chloroform. The extracts were washed with water dried over anhydrous magnesium sulfate and chromatographed on silica gel 37 g in chloroform. The eluent 1.497 g was recrystallized from acetone-isopropyl ether to give the titled compound (11) as pale gray crystals, 1.304 g, m.p. 90-91.5° C. Yield 70.1%.

¹H-NMR (CDCl₃): 1.26 (3H, t, J=7.2 Hz), 1.31 (3H, t, J=7.2 Hz), 4.05 (2H, s), 4.18 (2H, q, J=7.2 Hz), 4.28 (2H, q, J=7.2 Hz), 4.69 (2H, s), 6.36 (1H, dd, J=7.2, 0.9 Hz), 6.97-7.07 (3H, m), 8.07(1H, br s).

(2) 8-Hydroxy-2,7-dihydro-6-oxa-2-azabenzo[c,d]azulene-9-carboxylic acid ethyl-ester (12)

Compound (11) 754 mg was dissolved in dry tetrahydrofuran 20 ml. 60% Sodium hydride 217 mg was added to the solution of with cooling in ice. The mixture was stirred at room temperature for 1 h. To the ice-cold reaction mixture, ethanol 0.5 ml was added and the 2N HCl 3 ml was added to acidify. The mixture was extracted with ether. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel 45 g in chloroform. The eluent 198 mg was recrystallized from ether-isopropyl ether to give the titled compound (12) as colorless crystals 195 mg, m.p. 136-137° C. Yield 30.5%.

¹H-NMR. (CDCl₃): 1.44 (3H, t, J=7.2 Hz), 4.42 (2H, q, J=7.2 Hz), 4.75 (2H, s), 6.56-6.71 (1H, m), 7.02-7.09 (2H, m), 7.50 (1H, d, J=2.7 Hz), 8.20 (1H, br s), 13.02 (1H, s).

EXAMPLE 8

8-Methoxyl-2,7-dihydro-6-oxa-2-azabenzo[c,d]azulene-9-carboxylic acid ethyl ester (13)

A mixture of the compound obtained in Ex. 7 (12) 100 mg, methyl iodide 0.031 ml and potassium carbonate 9 mg in dimethylformamide 3 ml was stirred at room temperature for 15 h. Water was added and the mixture was extracted with ether. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel 6 g in chloroform. The eluent 102 mg was recrystallized from acetone-ether to give the titled compound (13) as colorless crystals 67 mg, m.p. 183-184 C.

Yield 63.8%.

¹H-NMR (CDCl₃): 1.24-1.29 (3H, m), 1.82 (3H, s), 4.16-4.35 (2H, m), 4.49 (1H, d, J=17.4 Hz), 5.02 (1H, d, J=17.4 Hz), 6.73-6.79 (1H, m), 6.96-6.97(1H, m), 7.02-7.13 (2H, m), 8.85 (1H, br s).

EXAMPLE 9

(1) 4-Ethoxycarbonylmethoxy-3-ethoxycarbonylmethyl-indole-1-carboxylic acid tert-butyl ester (14)

Compound (11) 1.40 g and di-tert-butyldicarbonate 1.05 g were dissolved in tetrahydrofuran 20 ml and 4-dimethylaminopyridine, 28 mg was added. The mixture was allowed to stand at room temperature overnight and concentrated under reduced pressure to remove tetrahydrofurane. The residue obtained was dissolved in toluene and chromatographed on silica gel 10 g in 5% ethyl acetate-toluene to give the titled compound (14) as a colorless oil, 1.789 g. Yield 96.2%.

¹H-NMR (CDCl₃): 1.26 (3H, t, J=7.2 Hz), 1.30 (3H, t, J=7.2 Hz), 1.65 (9H, s), 3.96 (2H, s), 4.18 (2H, q, J=7.2 Hz), 4.27 (2H, q, J=7.2 Hz), 4.67 (2H, s), 6.52 (1H, d, J=8.1 Hz), 7.18 (1H, t, J=8.1 Hz), 7.42 (1H, s), 7.80 (1H, d, J=8.1 Hz).

(2) 8-Hydroxy-7H-6-oxa-2-azabenzo[c,d]azulene-2,9-dicarboxlic acid 2-tert-butyl ester 9-ethyl ester (15)

Compound (14) 953 mg was dissolved in dry tetrahydrofuran 15 ml and 1.0 M solution of lithium bistrimethylsilylamide-tetrahydrofuran 3.5 ml was added to the solution with cooling in ice. The mixture was stirred at room temperature for 30 min. A solution of ammonium chloride 375 mg in water 5 ml was added with cooling in ice. The mixture was extracted with ether. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel 30 g in chloroform. The eluent 259 mg was recrystallized from ether-isopropyl ether to give the titled compound (15) as colorless crystals, m.p. 139.5-140.5° C., 236 mg. Yield 28.0%.

¹H-NMR (CDCl₃): 1.47 (3H, t, J=7.1 Hz), 1.68 (9H, s), 4.43 (2H, q, J=7.1 Hz), 4.73 (2H, s), 6.80 (1H, d, J=8.1 Hz), 7.18 (1H, t, J=8.1 Hz), 7.83 (1H, d, J=8.1 Hz), 7.87 (1H, s), 13.27 (1H, s).

EXAMPLE 10

(1) [3-Ethoxycarbonylmethyl-1-(toluene-4-sulfonyl)-1H-indol-4-yloxy]acetic acid ethyl ester (16)

Compound (11) 305 mg was dissolved in dry tetrahydrofuran 20 ml. 1.0 M Solution of lithium bistrimethylsilylamide-tetrahydrofuran 1.1 ml was added to the solution with cooling in dry ice-acetone bath at −70° C. After the mixture was stirred for 10 min, a solution of p-toluenesulfonyl chloride 229 mg in tetrahydrofuran 3 ml was added at that temperature. The mixture was stirred at room temperature for 2 h. A solution of ammonium chloride 59 mg in water 1 ml was added to the mixture, which was concentrated under reduced pressure to remove tetrahydrofuran. Water was added. The mixture was extracted with chloroform. The extracts were washed with water dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel 17 g in chloroform to give the titled compound (16) as a colorless oil 231 mg. Yield 50.2%.

¹H-NMR (CDCl₃): 1.24 (3H, t, J=7.2 Hz), 1.28 (3H, t, J=7.2 Hz), 2.34 (3H, s), 3.94 (2H, s), 4.16 (2H, q, J=7.2 Hz), 4.25 (2H, q, J=7.2 Hz), 4.62 (2H, s), 6.49 (1H, d, J=8.1 Hz), 7.17 (1H, t, J=8.1 Hz), 7.21 (2H, d, J=8.7 Hz), 7.44 (2H, d, J=8.7 Hz), 7.60 (1H, d, J=8.1 Hz), 7.74 (2H, d, J=8.7 Hz).

(2) 8-Hydroxy-2-(toluene-4-sulfonyl)-2,7-dihydro-6-oxa-2-azabenzo[c,d]-azulene-9-carboxlic acid ethyl ester (17)

Compound (16) 228 mg was dissolved in dry tetrahydrofuran 10 ml and 1.0 M solution of lithium bistrimethylsilylamide tetrahydrofuran 1.05 ml was added to the solution with cooling in ice. The mixture was stirred for 20 min. A solution of ammonium chloride 112 mg in water 1 ml was added to the mixture, which was acidified with dilute hydrochloric acid. The mixture was extracted with ether. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained 279 mg was chromatographed on silica gel 10 g in toluene to give the titled compound (17) as a pale yellow oil 61 mg. Yield 29.8%.

¹H-NMR (CDCl₃): 1.50 (3H, t, J=7.2 Hz), 2.35 (3H, s), 4.45 (2H, q, J=7.2 Hz), 4.68 (2H, s), 6.78 (1H, dd, J=7.8, 0.9 Hz), 7.17 (1H, t, J=7.8 Hz), 7.23 (2H, d, J=8.1 Hz), 7.67 (1H, dd, J=7.8, 0.9 Hz), 7.77 (2H, d, J=8.7 Hz) 7.80 (1H, s), 13.30 (1H, s). Scheme of Reactions, Examples 11-16

EXAMPLE 11

2,9-Dihydro-6-oxa-2-azabenzo[cd]azulen-8-one (18-1) (R⁷=R¹=H)

Triethylamine 10 ml and ethyl chlorocarbonate 5.6 ml were added to a solution of compound (5-1) 14.85 g in dry tetrahydrofuran 148 ml with cooling in ice-methanol bath. The mixture was stirred at that temperature for 30 min. Then, a solution sodium azide 8.97 g in water 59 ml was added dropwise. The mixture was stirred with cooling in ice for 4 h. To the reaction mixtures water was added. The mixture was extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to give a yellow solid. The residue obtained was suspended in dioxane 280 ml. After the suspension was heated under reflux for 20 min, 1N HCl 58.3 ml was added with cooling in ice. Again, the mixture was heated under reflux for 20 min and cooled in ice-bath. Water was added. The mixture was extracted with ether. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel 150 g in ethyl acetate hexane (1:4) to give brown crystals, which was recrystallized from ether-petroleum ether to give the titled compound 7.94 g, m.p. 128-129° C. Yield 61%.

¹H-NMR(CDCl₃): 4.11 (2H, d, J=0.6 Hz), 4.69 (2H, s), 6.72-6.79 (1H, m), 6.92-6.95 (1H, m), 7.07-7.14 (2H, m), 8.12 (1H, br s).

Following compounds were obtained, according to the similar treatment. Compd m.p. No R⁷ R¹¹ (° C.) ¹H-NMR(CDCl₃) 18-2 Me Me 136-139 2.32(3H, s), 2.33(3H, s), 3.99(2H, s), 4.66(2H, s), 6.89(1H, d, J=8.4Hz), 6.92(1H, d, J=8.4Hz), 7.77(1H, br s) 18-3 H Br 137-138 4.09(2H, d, J=1.2Hz), 4.75(2H, s), 6.95(1H, m), 7.01(1H, d, J=8.7Hz), 7.27(1H, d, J=8.7Hz), 8.14(1H, br s)

EXAMPLE 12

Dimethyl-(2,7,8,9-tetrahydro-6-oxo-2-azabenzo[cd]azulen-8-yl)amine (19-1)

-   -   (R⁷=R¹¹=H; R¹⁶=R¹⁷=Me)

Dimethylamine (2 mol/tetrahydrofuran solution), compound (18-1) 690 mg, sodium triacetoxyborohydride 1.17 g and acetic acid 226 mg were dissolved in tetrahydrofuran 28 ml with cooling in ice. The mixture was stirred at room temperature for 1 h and allowed stand overnight. To the reaction mixture, ice-water and an aqueous sodium hydrogen carbonate solution were added. The mixture was extracted with ether. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide 30 g in chloroform methanol (50:1) to give the titled compound as colorless crystals 689 mg. Yield 86%. This was recrystallized from ethyl acetate-hexane to give colorless crystals, m.p. 131-132.5° C. ¹H-NMR(CDCl₃): 2.42 (6H, s), 2.93-3.24 (3H, m), 4.15 (1H, dd, J=12.3, 6.6 Hz), 4.55 (1H, dd, J=12.3, 1.5 Hz), 6.62 (1H, dd, J=6.6, 0.9 Hz), 6.95-7.09 (3H, m), 8.14 (1H, br s).

Following compounds were obtained, according to the similar treatment. Compd No R⁷ R¹¹ R¹⁶ R¹⁷ m.p. (° C.) ¹H-NMR (CDCl₃) 19-2  H H H Me 112-116 2.56 (3H, s), 2.99-3.22 (3H, m), oxalate 4.27-4.38 (2H, m), 6.65 (1H, d, J=7.5 Hz), 6.96-7.09 (3H, m), 8.24 (1H, br s) 19-3  H H H nPr 137-139 0.93 (3H, t, J=7.5 Hz), 1.54 (2H, sex, J=7.5 Hz), 2.62-2.80 (2H, m), 2.92-3.02 (1H, m), 3.14-3.25 (2H, m), 4.19-4.30 (2H, m), 6.44-6.50 (1H, m), 6.90-7.02 (3H, m) CD₃OD 19-4  H H Et Et 123-124 1.12 (6H, t, J=7.5 Hz), 2.69 (4H, q, J=7.5 Hz), 2.90-3.00 (1H, m), 3.20-3.30 (2H, m), 4.08 (1H, dd, J=11.7, 6.3 Hz), 4.53 (1H, dd, J=11.7, 2.1 Hz), 6.41-6.48 (1H, m), 6.88-6.95 (2H, m), 7.01-7.03 (1H, m) CD₃OD 19-5  H H NPr nPr  60-61 0.90 (6H, t, J=7.5 Hz), 1.40-1.60 (4H, m), 2.40-2.60 (4H, m), 2.90-3.01 (1H, m), 3.15-3.35 (2H, m), 4.09 (1H, dd, J=12.3, 6.9 Hz), 4.61 (1H, dd, J=12.3, 1.8 Hz), 6.61 (1H, d, J=7.5 Hz), 6.95-6.98 (2H, m), 7.06 (1H, t, J=7.5 Hz), 8.06 (1H, br s) 19-6  H H H cyclohexyl 141-142 1.00-2.02 (10H, m), 2.64-2.74 (1H, m), 2.98 (1H, ddd, J=15.3, 8.4, 1.2 Hz), 3.14 (1H, dd, J=15.3, 3.6 Hz), 3.39-3.47 (1H, m), 4.23-4.32 (2H, m), 6.63 (1H, dd, J=7.5, 0.9 Hz), 6.95-6.99 (2H, m), 7.07 (1H, t, J=7.5 Hz), 8.11 (1H, br s) 19-7  H H H allyl 112-113 3.00-3.18 (2H, m), 3.28-3.49 (1H, m), 4.27-4.38 (2H, m), 5.08-5.13 (1H, m), 5.18-5.26 (1H, m), 5.86-5.99 (1H, m), 6.64 (1H, dd, J=7.8, 1.2 Hz), 6.95-7.00 (2H, m), 7.07 (1H, t, J=7.8 Hz), 8.11 (1H, br s) 19-8  H H H iPr 133-135 1.10 (3H, d, J=6.0 Hz), 1.11 (3H, d, J=6.0 Hz), 2.97-3.17 (3H, m), 3.35-3.42 (1H, m), 4.25-4.37 (2H, m), 6.64 (1H, dd, J=7.5, 0.9 Hz), 6.95-7.00 (2H, m), 7.07 (1H, t, J=7.5 Hz), 8.10 (1H, br s) 19-9  H H H

104-106 2.83 (2H, t, J=7.5 Hz), 2.95-3.17 (4H, m), 3.26-3.33 (1H, m), 4.29 (2H, d, J=3.6 Hz), 6.62 (1H, d, J=7.5 Hz), 6.93-7.00 (2H, m), 7.07 (1H, t, J=7.8 Hz), 7.18-7.30 (5H, m), 8.08 (1H, br s) 19-10 H H

137-139 1.80-1.89 (4H, m), 2.70-3.04 (6H, m), 3.37 (1H, d, J=14.4 Hz), 4.17 (1H, dd, J=12.3, 6.3 Hz), 4.59 (1H, dd, J=12.3, 2.1 Hz), 6.61 (1H, dd, J=7.5, 0.9 Hz), 6.95-6.99 (2H, m), 7.06 (1H, t, J=7.8 Hz), 8.10 (1H, br s) 19-11 H H

115-125 (dec.) oxalate 1.45-1.75 (6H, m), 2.50-2.80 (4H, m), 2.94-3.12 (2H, m), 3.24-3.31 (1H, m), 4.10 (1H, dd, J=12.0, 6.3 Hz), 4.63 (1H, dd, J=12.0, 1.8 Hz), 6.61 (1H, dd, J=7.8, 0.9 Hz), 6.94-6.98 (2H, m), 7.06 (1H, t, J=7.8 Hz), 8.10 (1H, br s) 19-12 H H

183-184 (dec.) oxalate 2.32 (3H, s), 2.40-2.60 (4H, m), 2.62-2.73 (2H, m), 2.80-2.90 (2H, m), 2.95-3.11 (2H, m), 3.22-3.30 (1H, m), 4.12 (1H, dd, J=12.3, 6.3 Hz), 4.60 (1H, dd, J=12.3, 2.1 Hz), 6.61 (1H, dd, J=7.8, 0.9 Hz), 6.95-6.99 (2H, m), 7.06 (1H, t, J=7.8 Hz), 8.12 (1H, br s) 19-13 H H

207-208 2.46-2.56 (2H, m), 2.62-2.72 (2H, m), 2.76-2.98 (2H, m), 3.08-3.18 (1H, m), 3.53-3.62 (4H, m), 4.06 (1H, dd, J=12.3, 6.6 Hz), 4.45 (1H, d, J=12.3 Hz), 6.40 (1H, dd, J=6.6, 2.1 Hz), 6.86-6.94 (2H, m), 7.11 (1H, d, J=1.8 Hz), 10.95 (1H, br s) DMSO-d₆ 19-14 H H H CH₂CH₂OH 154-157 2.85-3.11 (4H, m), 3.25-3.30 (2H, (dec.) m), 3.62 (2H, t, J=5.4 Hz), 4.26-4.42 oxalate (2H, m), 6.64 (1H, dd, J=7.5, 0.9 Hz), 6.96-7.10 (3H, m), 8.16 (1H, br s) 19-15 H Br H Me

2.58 (3H, s), 2.91-3.22 (3H, m),

4.34 (1H, dd, J=12.6, 6.9 Hz), 4.44 (1H, d, J=12.6 Hz), 6.86 (1H, d, J=8.4 Hz), 6.97 (1H, m), 7.28 (1H, d, J=8.4 Hz), 8.17 (1H, br s) 19-16 H Br Me Me 142-143 2.43 (6H, s), 2.92-3.23 (3H, m), 4.22 (1H, dd, J=12.3, 6.9 Hz), 4.67 (1H, dd, J=12.3, 1.8 Hz), 6.85 (1H, d, J=8.7 Hz), 6.98 (1H, m), 7.26 (1H, d, J=8.7 Hz), 8.13 (1H, br s) 19-17 Me Me Me Me 144-146 2.28 (3H, s), 2.34 (3H, s), 2.47 (6H, s), 2.82-3.11 (3H, m), 4.10 (1H, dd, J=12.0 Hz, 6.6 Hz), 4.58 (1H, d, J=12.0 Hz), 6.79 (1H, d, J=8.1 Hz), 6.87 (1H, d, J=8.1 Hz), 7.74 (1H, br s) 19-18 Me Me H Me 173-175 2.29 (3H, s), 2.31 (6H, s), 2.57 (3H, (dec.) s), 2.80-2.87 (1H, m), 2.97-3.03 oxalate (1H, m), 3.12-3.20 (1H, m), 4.29- 4.32 (2H, m), 6.79 (1H, d, J=8.1 Hz), 6.87 (1H, d, J=8.1 Hz), 7.79 (1H, br s), 19-19 H H H cyclopropyl 130-131 0.34-0.55 (4H, m), 2.27-2.34 (1H, m), 3.02-3.18 (2H, m), 3.38-3.44 (1H, m), 4.33-4.44 (2H, m), 6.65 (1H, dd, J=7.5, 0.9 Hz), 6.94-7.07 (3H, m), 8.27 (1H, br s) 19-20 H H H CH₂CF₃ 108-109 3.13 (2H, d, J=5.1 Hz), 3.27-3.44 (3H, m), 4.25 (1H, d, J=12.6 Hz), 4.40 (1H, dd, J=12.6, 6.9 Hz), 6.64 (1H, dd, J=8.1, 0.9 Hz), 6.98 (1H, s), 7.00 (1H, dd, J=8.1, 0.9 Hz), 7.08 (1H, t, J=8.1 Hz), 8.10 (1H, br s) 19-21 H H Me Et 122-124 1.13 (3H, t, J=7.2 Hz), 2.39 (3H, s), 2.54-2.79 (2H, m), 2.97-3.27 (3H, m), 4.12 (1H, dd, J=12.3, 6.3 Hz), 4.59 (1H, dd, J=12.3, 1.8 Hz), 6.62 (1H, dd, J=7.5, 0.9 Hz), 6.96-7.09 (3H, m), 8.12 (1H, br s) 19-22 H H H Et 139-141 1.14 (3H, t, J=7.2 Hz), 2.73-2.93 (2H, m), 3.00-3.19 (2H, m), 3.26- 3.33 (1H, m), 4.27-4.37 (1H, m), 6.64 (1H, dd, J=7.5, 0.9 Hz), 6.96-6.99 (2H, m), 7.07 (1H, t, J=7.5 Hz), 8.15 (1H, br s)

EXAMPLE 13

(Method 1)

(2-Benzenesulfonyl-2,7,8,9-tetrahydro-6-oxo-2-azabenzo[cd]azulen-8-yl)dimethylamine oxalate (20-1) (R⁷=R¹¹=H)

60% Sodium hydride 17 mg was added to a solution of compound (19-1) 75 mg in dry dimethylformamide 2.5 ml with cooling in ice. The mixture was stirred at 45° C. for 1 h. Benzenesulfonyl chloride 1 ml was added with cooling in ice. The mixture was stirred at room temperature for 21 h. Ice-water and an aqueous sodium hydrogen carbonate solution were added to the mixture, which was extracted with ether. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in chloroform hexane (1:2) to give the titled compound, 46 mg (yield 37%). This compound was treated with 1 eq. of oxalic acid to give the oxalic acid salt, which was recrystallized from ether-ethanol to give colorless crystals. m.p. 106-109° C. (dec.).

¹H-NMR(CDCl₃): 2.36 (6H, s), 2.80-3.12 (3H, m), 4.13 (1H, dd, J=12.3, 6.6 Hz), 4.42 (1H, dd, J=12.3, 0.6 Hz), 6.75 (1H, d, J=8.1 Hz), 7.14-7.20 (1H, m), 7.34 (1H, s), 7.41-7.61 (4H, m), 7.86-7.89 (2H, m)

Following compounds were obtained, according to the similar treatment. Comp No R⁷ R⁸ R¹¹ m.p. ¹H-NMR (CDCl₃) 20-2  H COPh H 126-129 2.40 (6H, s), 2.86-3.16 (3H, m), 4.20 (1H, (dec.) dd, J=12.3, 6.3 Hz), 4.50 (1H, d, J=12.3 oxalate Hz), 6.85 (1H, dd, J=7.2, 0.9 Hz), 7.06 (1H, s), 7.23-7.28 (1H, m), 7.49-7.63 (3H, m), 7.71 (2H, dd, J=8.4, 1.8 Hz), 8.04 (1H, dd, J=8.1, 0.9 Hz) 20-3  H CH₂Ph H 183-186 2.41 (6H, s), 2.88-3.06 (2H, m), 3.15-3.22 (dec.) (1H, m), 4.15 (1H, dd, J=12.0, 6.3 Hz), oxalate 4.54 (1H, dd, J=12.0, 1.8 Hz), 5.23 (2H, s), 6.61 (1H, dd, J=7.8, 0.6 Hz), 6.85- 6.89 (2H, m), 7.02-7.15 (3H, m), 7.25- 7.33 (3H, m) 20-4  H CH₂CONMe₂ H 119-124 2.40 (6H, s), 2.99 (3H, s), 3.04 (3H, s), (dec.) 2.88-3.22 (2H, m), 3.15-3.22 (1H, m), oxalate 4.13 (1H, dd, J=12.3, 6.6 Hz), 4.53 (1H, dd, J=12.3, 1.8 Hz), 4.82 (2H, s), 6.61 (1H, dd, J=8.1, 0.9 Hz), 6.79-7.10 (3H, m) 20-5  H

H 148-149 2.37 (6H, s), 2.89 (1H, m), 3.06-3.16 (2H, m), 4.15 (1H, dd, J=12.9, 6.9 Hz), 4.43 (1H, d, J=12.9 Hz), 6.71 (1H, dd, J=7.8, 0.6 Hz), 7.10 (1H, t, J=8.1 Hz), 7.39-7.67 (5H, m), 7.86-8.15 (3H, m), 8.76 (1H, d, J=8.7 Hz) 20-6  H

H 114-118 (dec.) oxalate 2.36 (6H, s), 2.81-3.11 (3H, m), 4.14 (1H, dd, J=12.6, 6.6 Hz), 4.43 (1H, d, J=12.6 Hz), 6.76 (1H, dd, J=7.8, 0.9 Hz), 7.18 (1H, t, J=8.4 Hz), 7.23 (1H, t, J=1.5 Hz), 7.38-7.42 (2H, m), 7.57 (1H, dd, J=8.4, 0.9 Hz), 7.77-7.82 (2H, m) 20-7  H SO₂Et H 153-155 1.23 (3H, t, J=7.5), 2.41 (6H, s), 2.87- (dec.) 3.14 (3H, m), 3.28 (3H, q, J=7,5 Hz), oxalate 4.22 (1H, dd, J=12.3, 6.6 Hz), 4.49 (1H, d, J=12.3 Hz), 6.82 (1H, d, J=7.8 Hz), 7.19-7.27 (2H, m), 7.50 (1H, J=8.4 Hz) 20-8  H IPr H 191-194 1.49 (3H, t, J=6.3 Hz), 1.50 (3H, t, (dec.) J=6.3 Hz), 2.42 (6H, s), 2.93-3.24 (3H, m), oxalate 4.13 (1H, dd, J=12.3, 6.6 Hz), 4.54 (1H, dd, J=12.3, 1.8 Hz), 4.57-4.66 (1H, m), 6.59 (1H, dd, J=7.8, 1.2 Hz), 6.94 (1H, d, J=7.5 Hz), 7.01 (1H, s), 7.07 (1H, d, J=7.8 Hz) 20-9  H

H 142-144 (dec.) oxalate 2.37 (6H, s), 2.81-3.10 (3H, m), 4.16 (1H, dd, J=12.3, 6.6 Hz), 4.43 (1H, dd, J=12.3 Hz), 6.78 (1H, d, J=8.4 Hz), 7.00 (1H, dd, J=4.8, 3.9 Hz), 7.21 (1H, t, J=8.4 Hz), 7.30 (1H, s), 7.53 (1H, dd, J=5.1, 1.5 Hz), 7.62 (1H, d, J=8.4 Hz), 7.67 (1H, dd, J=4.2, 1.5 Hz) 20-10 H

H 119-122 (dec.) oxalate 2.37 (6H, s), 2.82-2.88 (1H, m), 2.96-3.11 (2H, m), 4.16 (1H, dd, J=12.6, 6.6 Hz), 4.43 (1H, d, J=12.6 Hz), 6.78 (1H, dd, J=8.1, 0.9 Hz), 7.17-7.32 (2H, m), 7.59 (1H, dd, J=8.1, 0.6 Hz), 7.71 (2H, d, J=8.4 Hz), 8.00 (2H, d, J=8.1 Hz) 20-11 H

H 147-150 (dec.) oxalate 2.37 (6H, s), 2.82-3.12 (3H, m), 4.14 (1H, dd, J=12.6, 6.6 Hz), 4.43 (1H, d, J=12.6 Hz), 6.77 (1H, dd, J=7.8, 0.6 Hz), 7.18 (1H, t, J=8.1 Hz), 7.30 (1H, s), 7.55-7.58 (2H, m), 7.71-7.74 (2H, m) 20-12 H

H 168-171 (dec.) oxalate 2.37 (6H, s), 2.81-3.11 (3H, m), 4.16 (1H, dd, J=12.3, 6.6 Hz), 4.42 (1H, d, J=12.3 Hz), 6.77 (1H, dd, J=8.1, 0.3 Hz), 7.20 (1H, t, J=8.1 Hz), 7.30-7.34 (2H, m), 7.57 (1H, d, J=8.1 Hz), 7.64-7.81 (2H, m), 8.01 (1H, t, J=1.8 Hz) 20-13 H

H 173-176 (dec.) oxalate 2.40 (6H, s), 2.86-3.11 (3H, m), 4.21 (1H, dd, J=12.3, 6.6 Hz), 4.60 (1H, d, J=12.3 Hz), 6.75 (1H, dd, J=8.1, 0.6 Hz), 7.09 (1H, t, J=8.1 Hz), 7.23-7.26 (1H, m), 7.36-7.50 (2H, m), 7.55 (1H, s), 7.67 (1H, dd, J=7.8, 1.5 Hz), 8.09 (1H, dd, J=7.8, 1.5 Hz) 20-14 H

H 140-142 (dec.) oxalate 2.37 (6H, s), 2.81-3.11 (3H, m), 3.80 (3H, s), 4.13 (1H, dd, J=12.3, 6.6 Hz), 4.43 (1H, d, J=12.3 Hz), 6.74 (1H, d, J=8.1 Hz), 6.88 (2H, dd, J=6.9, 2.1 Hz), 7.17 (1H, t, J=8.4 Hz), 7.33 (1H, s), 7.58 (1H, d, J=8.1 Hz), 7.82 (1H, dd, J=6.9, 2.1 Hz) 20-15 H

H 123-126 (dec.) oxalate 2.37 (6H, s), 2.82-3.11 (3H, m), 3.85 (3H, s), 3.87 (3H, s), 4.14 (1H, dd, J=12.3, 5.7 Hz), 4.44 (1H, d, J=12.3 Hz), 6.75 (1H, dd, J=7.8, 0.9 Hz), 6.84 (2H, d, J=8.7 Hz), 7.17 (1H, t, J=8.1 Hz), 7.26-7.32 (2H, m), 7.51 (1H, dd, J=8.4, 2.1 Hz), 7.61 (1H, dd, J=8.4, 0.6 Hz) 20-16 H

H 169-171 (dec.) oxalate 2.39 (6H, s), 2.85-3.13 (3H, m), 4.19 (1H, dd, J=12.6, 6.3 Hz), 4.46 (1H, d, J=12.6 Hz), 6.74 (1H, d, J=15.3 Hz), 6.80 (1H, dd, J=8.4, 0.6 Hz), 7.20 (1H, t, J=8.4 Hz), 7.27-7.45 (6H, m), 7.52 (1H, dd, J=8.1, 0.9 Hz), 7.70 (1H, d, J=15.5 Hz) 20-17 H

H 161-163 (dec.) oxalate 2.39 (6H, s), 2.84-3.09 (3H, m), 4.21 (1H, dd, J=12.3, 5.4 Hz), 4.44 (1H, d, J=12.3 Hz), 6.77 (1H, dd, J=8.4, 0.9 Hz), 7.13 (1H, t, J=8.4 Hz), 7.25 (1H, dd, J=8.1, 0.9 Hz), 7.35 (1H, d, J=8.4 Hz), 7.43-7.48 (2H, m), 8.19 (1H, d, J=2.4 Hz) 20-18 H SO₂Ph Br 89-90 2.39 (6H, s), 2.85-3.10 (3H, m), 4.24 (1H, dd, J=12.3, 6.3 Hz), 4.54 (1H, d, J= 12.3 Hz), 7.34 (1H, s), 7.39-7.59 (5H, m), 7.84-7.87 (2H, m) 20-19 H

H 143-144 (dec.) oxalate 2.37 (6H, s), 2.82-2.88 (1H, m), 2.96-3.11 (2H, m), 4.15 (1H, dd, J=12.6, 6.6 Hz), 4.42 (1H, d, J=12.6 Hz), 6.76 (1H, d, J=7.8 Hz), 7.08-7.21 (3H, m), 7.25 (1H, dd, J=8.1, 0.9 Hz), 7.31 (1H, s), 7.56 (1H, d, J=8.4 Hz), 7.87-7.92 (2H, m) 20-20 H

H 128-131 (dec.) oxalate 2.40 (6H, s), 2.85-2.91 (1H, m), 3.07-3.10 (2H, m), 4.21 (1H, dd, J=12.6, 6.6 Hz), 4.44 (1H, d, J=12.6 Hz), 6.79 (1H, dd, J=8.1, 0.9 Hz), 7.12 (1H, t, J=8.1 Hz), 7.33-7.42 (3H, m), 7.78 (1H, dd, J=7.2, 6.0 Hz) 20-21 H

H 154-156 (dec.) oxalate 2.38 (6H, s), 2.83-3-13 (3H, m), 4.18 (1H, dd, J=12.6, 6.6 Hz), 4.44 (1H, d, J=12.6 Hz), 6.80 (1H, dd, J=8.1, 0.6 Hz), 6.83 (1H, d, J=4.2 Hz), 7.19-7.25 (2H, m), 7.46 (1H, d, J=4.1 Hz), 7.56 (1H, dd, J=8.1, 0.6 Hz) 20-22 H

H 163-164 (dec.) oxalate 2.38 (6H, s), 2.82-3-09 (3H, m), 4.19 (1H, dd, J=12.3, 6.3 Hz), 4.44 (1H, d, J=12.3 Hz), 6.75-7.03 (3H, m), 7.13 (1H, t, J=8.1 Hz), 7.38-7.41 (2H, m), 8.02-8.11 (1H, m) 20-23 H

H 147-150 (dec.) oxalate 2.39 (6H, s), 2.84-3-10 (3H, m), 3.66 (3H, s), 3.82 (3H, s), 4.18 (1H, dd, J=12.3, 6.6 Hz), 4.44 (1H, d, J=12.3 Hz), 6.72 (1H, dd, J=8.1, 0.9 Hz), 6.81 (1H, d, J=9.0 Hz), 7.04 (1H, dd, J=9.0, 3.3 Hz), 7.09 (1H, t, J=8.1 Hz), 7.36 (1H, d, J=8.1 Hz), 7.43 (1H, s), 7.60 (1H, d, J=3.3 Hz) 20-24 H

H 103-104 2.37 (6H, s), 2.82-3-12 (3H, m), 3.79 (3H, s), 3.82 (3H, s), 4.15 (1H, dd, J=12.6, 6.6 Hz), 4.43 (1H, d, J=12.6 Hz), 6.75 (1H, dd, J=8.1, 0.6 Hz), 7.03-7.07 (1H, m), 7.17 (1H, t, J=8.1 Hz), 7.31-7.46 (4H, m), 7.60 (1H, dd, J=8.1, 0.6 Hz) 20-25 H

H 113-115 (dec.) oxalate 2.32 (6H, s), 2.81-3.12 (3H, m), 4.17 (1H, dd, J=12.6, 6.3 Hz), 4.44 (1H, d, J=12.6 Hz), 6.46 (1H, d, J=1.8 Hz), 6.80 (1H, d, J=7.8 Hz), 7.24 (1H, t, J=8.1 Hz), 7.29 (1H, d, J=3.9 Hz), 7.33 (1H, d, J=3.9 Hz), 7.61 (1H, d, J=7.8 Hz), 7.64 (1H, d, J=3.9 Hz), 8.27 (1H, d, J=1.8 Hz) 20-26 H SO₂Ph H 95-98 1.09 (3H, t, J=7.2 Hz), 2.34 (3H, s), (*) (dec.) 2.50-2.74 (2H, m), 2.91-3.16 (3H, m), oxalate 4.05 (1H, dd, J=12.0, 6.6 Hz), 4.51 (1H, dd, J=12.0, 0.9 Hz), 6.74 (1H, dd, J= 8.1, 0.6 Hz), 7.17 (1H, t, J=8.1 Hz), 7.34 (1H, s), 7.41-7.61 (5H, m), 7.86- 7.89 (2H, m) 20-27 Me SO₂Ph Me 155-158 2.24 (3H, s), 2.39 (6H, s), 2.52 (3H, s), (dec.) 4.05 (1H, dd, J=12.6, 5.7 Hz), 4.46 (1H, oxalate d, J=12.6 Hz), 7.01 (1H, d, J=8.7 Hz), 7.38-7.43 (2H, m), 7.49-7.55 (1H, m), 7.71-7.77 (3H, m) (*) 20-26; R⁴=N(Me)Et (Method 2) (2-Benzenesulfonyl-2,7,8,9-tetrahydro-6-oxo-2-aza-benzo[cd]azulen-8-yl)-dimethylamine (20-1)

n-BuLi (1.56 mol/l hexane solution) 1.39 ml was added to a solution of compound (19-1) 432 mg in dry tetrahydrofuran 10 ml at −70° C. under nitrogen atmosphere. The solution was stirred at that temperature for 1 h and at −30° C. for 1 h. Then, the temperature was again lowered to −70° C. and benezenesulofonyl chloride 396 mg was added dropwise. The reaction temperature was allowed to raise gradually to the room temperature. The mixture was stirred at room temperature, poured to ice and an aqueous ammonium chloride solution and extracted with chloroform. The chloroform layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was choromatographed on aluminum oxide 12 g in chloroform: hexane (8:1) to give the titled compound as crystals. Yield 83%. The product was recrystallized from ethyl acetate isopropyl ether to give colorless crystals. m.p. 114-116° C.

¹H-NMR(CDCl₃): 2.36 (6H, s), 2.80-3.12 (3H, m), 4.13 (1H, dd, J=12.3, 6.6 Hz), 4.42 (1H, dd, J=12.3, 0.6 Hz), 6.75 (1H, d, J=8.1 Hz), 7.14-7.20 (1H, m), 7.34 (1H, s), 7.41-7.61 (4H, m), 7.86-7.89 (2H, m)

EXAMPLE 14

(1-Bromo-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)dimethylamine (21),

(1,5-Dibromo-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)dimethyl-amine (22) and

(1,3-Dibromo-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)dimethyl-amine (23)

N-Bromosuccinimide 214 mg was added to a warm solution of compound (19-1) 216 mg in carbon tetrachloride 33 ml and the mixture was heated under reflux for 2 h. After the reaction ceased, the insoluble materials were removed by filtration and washed with chloroform. The filtrate was concentrated under reduced pressure. The residue obtained was chromatographed on silica gel in chloroform:methanol (30:1). The eluent was chromatographed on thin silica gel plates in chloroform:methanol (30:1) to give the titled compound (21) 51 mg. Yield 17%. This was recrystallized from ethyl acetate-ether to give crystals, m.p. 170-172 C.

¹H-NMR(CDCl₃): 2.43 (6H, s), 2.88-3.08 (3H, m), 4.15 (1H, dd, J=12.3, 6.0 Hz), 4.52 (1H, d, J=12.3 Hz), 6.62 (1H, dd, J=7.8, 0.9 Hz), 6.89 (1H, dd, J=8.1, 0.9 Hz), 7.04 (1H, t, J=7.8 Hz), 8.07 (1H, br s)

1,5-Dibromo compound (22) 15 mg was isolated from another fraction. Yield 4% Purifying from ether gave crystals, m.p. 123-126° C.

¹H-NMR(CDCl₃): 2.44 (6H, s), 2.84-3.08 (3H, m), 4.21 (1H, dd, J=12.0, 6.9 Hz), 4.66 (1H, d, J=12.0 Hz), 6.78 (1H, d, J=8.7 Hz), 7.25 (1H, d, J=8.7 Hz), 8.49 (1H, br s)

The mother liquor of the above mentioned 1,5-dibromo compound (22) was concentrated under reduced pressure and again chromatographed on thin silica gel plates in chloroform:methanol (30:1) to give the 1,3-dibromo compound (23) 8 mg (yield 2%). This was treated with 1 eq. oxalic acid to give the salt, m.p. 147-152° C. (dec.).

¹H-NMR(CDCl₃): 2.42 (6H, s), 2.90-3.05 (3H, m), 4.09-4.16 (1H, m), 4.50 (1H, d, J=12.0 Hz), 6.53 (1H, d, J=8.1 Hz), 7.15 (1H, d, J=8.1 Hz), 8.22 (1H, br s)

EXAMPLE 15

2-Chloro-N-(2, 7,8,9-tetrahydro-6-oxo-2-azabenzo[cd]azulen-8-yl)acetamide (24-1)

-   -   (R=COCH₂Cl):

Compound (8-1) 535 mg was dissolved in dry tetrahydrofuran 15 ml. Triethylamine 345 mg and chloroacetyl chloride 0.25 ml were added to the solution with cooling in ice. The mixture was stirred for 1 h and at room temperature for 30 min. Ice-water was added to the mixture with cooling in ice. The mixture was extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel 25 g in ethyl acetate:hexane (2:1) to give the titled compound 706 mg (94%) as a colorless oil.

¹H-NMR(CDCl₃): 3.06-3.14 (1H, m), 3.36-3.43 (1H, m), 3.95-4.06 (2H, m), 4.08-4.16 (1H, m), 4.27 (1H, d, J=11.4 Hz), 4.54-4.64 (2H, m), 6.70 (1H, dd, J=7.5, 1.2 Hz), 6.99 (1H, s), 7.03-7.13 (2H, m), 8.18 (1H, br s)

Following compounds were obtained, according to the similar treatment. Compd No R m.p. ¹H-NMR(CDCl₃) 24-2 COOMe Colorless 3.02-3.07(1H, m), 3.33-3.39(1H, m), 3.63(3H, s), oil 4.23(1H, d, J=9.3Hz), 4.34-4.41(1H, m), 4.53-4.60(1H, m), 5.25(1H, br d), 6.67(1H, d, J=7.8Hz), 6.97(1H, s), 7.00-7.11(2H, m), 8.14(1H, br s) 24-3 Ms Colorless 3.02(3H, s), 3.07-3-14(1H, m), 3.35-3.42(1H, m), oil 4.19-4.27(2H, m), 4.54-4.61(1H, m), 4.84(1H, d, J=8.7Hz), 6.68(1H, d, J=7.5Hz), 7.00-7.12(3H, m), 8.22(1H, br s) 24-4 SO₂NHMe Yellow 2.70(3H, d, J=5.4Hz), 3.04-3.11(1H, m), 3.35-3.42(1H, oil m), 4.03-4.28(3H, m), 4.53-4.60(1H, m), 4.81(1H, d, J=8.4Hz), 6.67(1H, dd, J=7.2, 1.2Hz), 6.98-7.11(3H, m), 8.24(1H, br s) 24-5 COMe 174-176 1.92(3H, s), 2.99-3.06(1H, m), 3.35-3.41(1H, m), 4.21-4.25(1H, m), 4.53-4.68(2H, m), 6.03(1H, br s), 6.69(1H, d, J=7.2Hz), 6.98(1H, s), 7.03-7.13(2H, m), 8.21(1H, br s)

EXAMPLE 16

2-Cyclohexylamino-N-(2,7,8,9-tetrahydro-6-oxo-2-azabenzo[cd]azulen-8-15 yl)acetamide (25-1)

A solution of compound (24-1) 160 mg and cyclohexylamine 360 mg in benzene 4 ml and methanol 4 ml was heated at 60° C. for 21 h and concentrated under reduced pressure. Water was added to the residue obtained. The mixture was extracted with chloroform. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel in ethyl acetate methanol (30:1) to give the titled compound 161 mg as crystals. Yield 81%. The crude crystalline materials were recrystallized from methanol-ethyl acetate to give colorless crystals, m.p. 184-186° C.

¹H-NMR(CDCl₃): 0.43-1.04 (4H, m), 1.22-1.57 (6H, m), 1.98-2.07 (1H, m), 3.02-3.46 (4H, m), 4.24-4.29 (1H, m), 4.54-4.59 (2H, m), 6.69 (1H, dd, J=7.5, 0.9 Hz), 6.96-7.11 (3H, m), 7.96 (1H, br s), 8.13 (1H, br s)

Following compounds were obtained, according to the similar treatment. Compd No R m.p. ¹H-NMR(CDCl₃) 25-2 NMe₂ 161-162.5 2.06(6H, s), 2.84-2.96(2H, m), 3.06-3.13(1H, m), 3.31-3.39(1H, m), 4.26(1H, d, J=11.4Hz), 4.52-4.62(2H, m), 6.68(1H, dd, J=7.5, 0.9Hz), 6.97-7.11(3H, m), 7.53(1H, br s), 8.21(1H, br s) (Scheme of Reactions, Examples 17-25)

EXAMPLE 17

((R)-1-Phenylethyl)-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-ylamine (26)

Sodium triacetoxyborohydride 318 mg and acetic acid 57 μl were added to a solution of compound (18-1) 187.6 mg and (R)-(+)-α-methylbenzylamine 13.7 mg in dry tetrahydrofuran 8 ml at room temperature and the mixture was stirred for 18 h. Water was added. The reaction mixture was made alkaline with an aqueous saturated sodium hydrogencarabonate solution and extracted with ether. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide 40 g in ethyl acetate:hexane (1:2) to give the titled compound 250 mg as a colorless oil. Yield 86%. The ¹H-NMR shows the titled compound is a mixture of their diastereomers.

¹H-NMR(CDCl₃): 1.33 (total 6H, d, J=6.6 Hz), 2.98-3.22 (total 6H, m), 4.04-4.41 (total 6H, m), 6.61-6.65 (total 2H, m), 6.91-7.41 (total 16H, m), 8.07 (total 2H, br s).

EXAMPLE 18

2,2,2-Trifluoro-N-((R)-1-phenylethyl)-N—(S)-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-ylacetamide (27) and 2,2,2-Trifluoro-N-((R)-1-phenylethyl)-N—(R)-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-ylacetamide (28)

Compound (26) 2.548 g was dissolved in dry tetrahydrofuran 8 ml. A solution of triethylamine 1.34 ml and trifluoroacetic anhydride 2.014 g in dry tetrahydrofuran 1 ml was added to the solution with cooling in ice. The mixture was stirred for 1 h. Furthermore, triethylamine 177 mg, trifluoroacetic anhydride 366 mg were added and the mixture was stirred for 1 h with cooling in ice. The solvents were removed by distillation under reduced pressure. Water was added to the residue. The mixture was extracted with ether. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel in ethyl acetate:hexane (1:5) repeatedly to give the titled compound (27) as a colorless oil, 990 mg (yield 29%) and the titled compound (28) as a colorless oil 1.672 g (yield 49%).

Compound (27)

¹H-NMR(CDCl₃): 1.82 (3H, d, J=6.9 Hz), 2.07-2.19 (1H, m), 3.54-3.66 (2H, m), 4.43 (1H, dd, J=12.9, 2.4 Hz), 4.81 (1H, dd, J=12.9, 6.0 Hz), 5.40 (1H, q, J=6.9 Hz), 6.61 (1H, dd, J=7.5, 0.9 Hz), 6.64 (1H, m)/6.94 (1H, dd, J=7.5, 0.9 Hz), 7.04 (1H, t, J=7.5 Hz), 7.27-7.40 (5H, m), 7.96 (1H, br s).

Compound (28)

¹H-NMR(CDCl₃): 1.72 (3H, d, J=6.9 Hz), 3.00-3.08 (1H, m), 3.55-3.63 (1H, m), 3.85-3.96 (1H, m), 4.10 (1H, dd, J=12.6, 2.4 Hz), 4.63 (1H, dd, J=12.6, 6.3 Hz), 5.39 (1H, q, J=6.9 Hz), 6.43 (1H, dd, J=7.5, 1.2 Hz), 6.91-7.01 (3H, m), 7.34-7.44 (5H, m), 8.08 (1H, br s).

EXAMPLE 19

((R)-1-Phenylethyl)-(S)-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-ylamine (29)

Compound (27) 934 mg was dissolved in ethanol 19 ml and sodium borohydride 364 mg was added to the solution at room temperature. The mixture was stirred for 17 h. Water was added with cooling in ice. The mixture was extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel in ethyl acetate:hexane (1:1) to give the titled compound (29) 695 mg. Yield 99.9%. Furthermore, the titled compound (29) was treated with a solution of hydrogen chloride in methanol to give the HCl salt, which was recrystallized from methanol-isopropanol to give colorless crystals, m.p. 233-240° C. (dec.). The absolute configuration was determined by an X-ray crystal structure analysis on a single crystal.

¹H-NMR(CDCl₃): 1.33 (3H, d, J=6.3 Hz), 3.00-3.22 (3H, m), 4.03 (1H, q, J=6.3 Hz), 4.21 (1H, d, J=11.7 Hz), 4.29-4.36 (1H, m), 6.63 (1H, dd, J=7.8, 0.9 Hz), 6.95-6.99 (2H, m), 7.06 (1H, t, J=7.8 Hz), 7.20-7.42 (5H, m), 8.07 (1H, br s).

According to the similar manner, ((R)-1-Phenylethyl))—(R)-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-ylamine (30) was obtained.

¹H-NMR(CDCl₃): 1.33 (3H, d, J=6.6 Hz), 2.80-3.15 (3H, m), 4.11 (1H, q, J=6.3 Hz), 4.26 (1H, d, J=12.0 Hz), 4.37 (1H, dd, J=12.0, 6.3 Hz), 6.64 (1H, dd, J=7.8, 0.9 Hz), 6.91-6.93 (1H, m), 6.96 (1H, dd, J=7.8, 0.9 Hz), 7.06 (1H, t, J=7.8 Hz), 7.20-7.41 (5H, m), 8.06 (1H, br s).

EXAMPLE 20

(S)-2,7,8,9-Tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-ylamine (31)

Compound (29) 609 mg was dissolved in tetrahydrofuran 20 ml. 20% Palladium(II)hydroxide 200 mg was added. A mixture was stirred in a hydrogen atomosphere for 22 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in chloroform to give the titled compound (31) as pale brown crystals, 337 mg.

Yield 86%. Furthermore, this was recrystallized from methanol-isopropanol to give the titled compound (31) as pale brown crystals, m.p. 202-203° C.

[α]_(D)+38.7±1.6° (C=0.509, methanol, 25° C.)

According to the similar manner, (R)-2,7,8,9-Tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-ylamine (32) was obtained.

m.p. 202-203° C., [a]_(D)−38.8±1.6° (C=0.508, methanol, 25° C.)

EXAMPLE 21

2,9-Dihydro-6-oxa-2-azabenzo[cd]azulen-8-one ethylene ketal (33)

Ethylene glycol 2.56 g and pyridinium p-toluenesulfonate 250 mg were added to a solution of compound (18-1) 1.877 g in benzene 50 ml. The mixture was heated under reflux for 14 h by use of a Dean-Stark apparatus. The reaction mixture separated into two layers. The upper layer was separated by decantation. Water and dioxane were added to the remained black oily part. The insoluble materials were removed by filtration and the filtrate was extracted with toluene. The extracts were washed with brine, treated with char coal, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give brown crystals. The above obtaied upper layer was washed with water, an aqueous saturated sodium hydrogen carbonate solution and brine successively, treated with char-coal and dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give colorless crystals. The combined crystals were recrystallized from tetrahydrofuran to give the titled compound (33) as colorless crystals, m.p. 200-202° C., 925 mg. Yield 40%.

¹H-NMR(DMSO-d₆): 3.16 (2H, s), 3.97 (4H, s), 4.13 (2H, s), 6.41 (1H, dd, J 6.6, 1.8 Hz), 6.88-6.96 (2H, m), 7.07 (1H, m), 10.94 (1H, br s).

EXAMPLE 22

2-Benzenesulfonyl-2,9-dihydro-6-oxa-2-azabenzo[cd]azulen-8-one ethylene ketal (34) 60% Sodium hydride 33 mg was added to a solution of compound (33) in dry dimethylformamide 2 ml with cooling in ice and the mixture was stirred for 10 min. Then, benzenesulfonyl chloride 152 mg was added. The mixture was heated at 60° C. for 14 h. Ice-water was added to the reaction mixtures, which was extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was choromatographed on aluminum oxide in chloroform hexane (1:1) to give the titled compound (34) as a pale yellow oil, 187 mg. Yield 69%.

¹H-NMR(CDCl₃): 3.22 (2H, s), 4.07 (4H, s), 4.16 (2H, s), 6.80 (1H, dd, J=8.1, 0.9 Hz), 7.18 (1H, t, J=8.1 Hz), 7.33 (14, m), 7.42-7.58 (3H, m), 7.62 (1H, dd, J=8.4, 0.9 Hz), 7.88-7.92 (2H, m).

EXAMPLE 23

2-Benzenesulfonyl-2,9-dihydro-6-oxa-2-azabenzo[cd]azulen-8-one (35)

Trifluoroacetic acid 1 ml and water 0.1 ml were added to compound (34) 48.4 mg. The mixture was heated at 80° C. for 15 min and concentrated under reduced pressure. Ice-water was added to the residue, which was made alkaline with an aqueous saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on silica gel in ethyl acetate:hexane (1:2) to give the titled compound (35) as a colorless oil, 33.2 mg. Yield 78%.

¹H-NMR(CDCl₃): 4.03 (2H, d, J=1.2 Hz), 4.62 (2H, s), 6.90 (1H, dd, J=7.8, 0.6 Hz), 7.25 (1H, t, J=7.8 Hz), 7.30 (1H, m), 7.44-7.61 (3H, m), 7.73 (1H, dd, J=7.8, 0.6 Hz), 7.88-7.93 (2H, m).

EXAMPLE 24

2-Benzenesulfonyl-8-pyrrolidin-1-yl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulene (36-1) (R⁴=pyrrolidinyl)

A solution of pyrrolidine 35.4 mg in dry tetrahydrofuran 0.5 ml, sodium triacetoxyborohydride 133.7 mg and acetic acid 26 μl were added to a solution of compound (35) 135.9 mg in dry tetrahydrofuran 3.5 ml at room temperature and the mixture was stirred for 24 h. Water was added to the reaction mixture, which was made alkaline with an aqueous saturated sodium hydrogencarbonate solution and extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide 20 g in chloroform to give the titled compound (36-1) as a brown oil, 97.7 mg. Yield 62%. This was treated with 1 eq. oxalic acid to give the salt which was recrystallized from ether-methanol to give colorless crystals, m.p. 170-173° C. (dec.).

¹H-NMR(CDCl₃): 1.76-1.84 (4H, m), 2.60-3.26 (7H, m), 4.12 (1H, dd, J=12.9, 6.3 Hz), 4.47 (1H, d, J=12.9 Hz), 6.73 (1H, dd, J=8.1, 0.9 Hz), 7.17 (1H, t, J=8.1 Hz), 7.33 (1H, s), 7.41-7.61 (4H, m), 7.86-7.90 (2H, m).

Following compounds were obtained, according to the similar treatment. Compd No R⁴ m.p. (° C.) ¹H-NMR(CDCl₃) 36-2 NHMe 208-213 2.52(3H, s), 2.91-3.15(3H, m), 4.22-4.27(2H, m), 6.76(1H, (dec.) dd, J=8.1, 0.9Hz), 7.18(1H, t, J=8.1Hz), 7.32-7.34(1H, oxalate m), 7.41-7.58(3H, m), 7.61(1H, dd, J=8.1, 0.9Hz), 7.86-7.90(2H, m) 36-3 NEt₂ 106-108 1.07(6H, t, J=6.9Hz), 2.50-3-30(7H, m), 3.98-4.05(1H, m), 4.52(1H, d, J=11.7Hz), 6.74(1H, dd, J=7.8, 0.9Hz), 7.17(1H, t, J=7.8Hz), 7.33(1H, s), 7.42-7.62(4H, m), 7.86-7.90(2H, m) 36-4 NHBn 208-209 2.94-3.11(2H, m), 3.20-3.27(1H, m), 3.86(1H, d, J=13.2Hz), (dec.) 3.95(1H, d, J=13.2Hz), 4.27(2H, d, J=3.9Hz), oxalate 6.77(1H, d, J=7.8Hz), 7.15-7.62(11H, m), 7.86-7.90(2H, m)

EXAMPLE 25

2,7,8,9-Tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-ol(37)

Compound (18-1) 374.4 mg was suspended in methanol 5 ml and sodium borohydride 75.7 mg was added to the suspension with cooling in ice. The mixture was stirred for 1 h. Water was added with cooling in ice. The mixture was extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was recrystallized from acetone-isopropanol to give the titled compound (37) as colorless crystals m.p. 169-170° C., 356.5 mg. Yield 94%.

¹H-NMR(CD₃OD): 2.83-2.93 (1H, m), 3.29-3.38 (1H, m), 4.03-4.17 (2H, m), 4.32 (1H, dd, J=5.4, 2.1 Hz), 6.42-6.48 (1H, m), 6.88-6.95 (1H, m), 6.99 (1H, br s). (Scheme of reactions, Examples 26-34)

EXAMPLE 26

Dimethyl-(5-phenyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)amine (38)

Phenylboronic acid 190.1 mg, palladium acetate 13.0 mg, tris(2-methylphenyl)phosphine 30.9 mg and potassium carbonate 691.0 mg were added to a solution of compound (19-16) 296 mg in dry dimethylformamide 6 ml under nitrogen atmosphere. The mixture was heated at 120 C for 2 h. After cooling, water was added. The mixture was extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in ethyl acetate:toluene (1:2) to give the titled compound (38) as colorless crystals, 33.0 mg. Yield 11%. Furthermore, the titled compound was recrystallized from acetone-isopropyl ether to give colorless crystals, m.p. 168-170° C.

¹H-NMR(CDCl₃): 2.42 (6H, s), 2.96-3.28 (3H, m), 4.17 (1H, dd, J=12.3, 6.3 Hz), 4.53 (1H, d, J=12.3 Hz), 7.02 (1H, s), 7.03 (1H, d, J=8.4 Hz), 7.15 (1H, d, J=8.4 Hz), 7.27-7.60 (5H, m).

EXAMPLE 27

(E)-3-(8-Dimethylamino-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-5-yl)-acrylic acid methyl ester (39)

Methyl acrylate 140 μl, triethylamine 217 μl and bis(triphenylphosphine)palladium dichloride 0.2 mg were added to a solution of compound (19-16) 306 mg in dry dimethylformamide 5 ml under nitrogen atmosphere. The mixture was heated at 100° C. for 19 h. Water was added with cooling in ice. The mixture was extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in ethyl acetate:hexane (11) to give the titled compound as yellow crystals 146.5 mg. Yield 47%. The titled compound was recrystallized from acetone-isopropyl ether to give pale yellow crystals, m.p. 168-170° C.

¹H-NMR(CDCl₃): 2.43 (6H, s), 2.90-3.22 (3H, m), 3.80 (3H, s), 4.24 (1H, dd, J=12.0, 6.6 Hz), 4.63 (1H, dd, J=12.6, 0.9 Hz), 6.39 (1H, d, J=16.2 Hz), 6.94 (1H, d, J=8.7 Hz), 6.97 (1H, m), 7.34 (1H, d, J=8.7 Hz), 8.22 (1H, br s), 8.25 (1H, d, J=16.2 Hz).

EXAMPLE 28

Dimethyl-(5-vinyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl) amine (40)

Tri-n-butylvinyltin 952.0 mg, tetrakistriphenylphosphinepalladium 116.1 mg and lithium chloride 254.0 mg were added to a solution of compound (19-16) 592.2 mg in dry dimethylformamide 30 ml under a nitrogen atmosphere. The mixture was heated at 120° C. for 4 h and diluted with ethyl acetate, after cooling. The insoluble materials were removed by filtration through cerite. The filtrate was washed with an aqueous saturated sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in ethyl acetate: toluene (1:2) to give a colorless oil 602.2 mg. This was chromatographed on silica gel in chloroform methanol: aq. ammonia (46:10:1). to give a yellow oil 500 mg, which was crystallized from hexane giving the titled compound as colorless crystals, 324 mg. Yield 67%. Furthermore, the titled compound was recrystallized from ether-petroleumether to give colorless crystals, m.p. 119-120° C.

¹H-NMR(CDCl₃): 2.43 (6H, s), 2.93-3.23 (3H, m), 4.12-4.19 (1H, m), 4.61 (1H, dd, J=12.6, 1.5 Hz), 5.13 (1H, dd, J=11.4, 1.5 Hz), 5.62 (1H, dd, J=18.0, 1.5 Hz), 6.91-6.96 (2H, m), 7.22 (1H, dd, J=18.0, 11.4 Hz), 7.34 (1H, d, J=8.4 Hz), 8.08 (1H, br s).

EXAMPLE 29

(5-Ethyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl) dimethylamine (41)

Compound (40) 242 mg was dissolved in methanol 4 ml and 5% palladium/C 60 mg was added. A mixture was stirred in hydrogen atmosphere at room temperature for 3 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in ethyl acetate:hexane (1:2) to give the titled compound as colorless crystals 241.6 mg.

Yield 99%. This was recrystallized from acetone-hexane to give the titled compound as colorless crystals, m.p. 91-92° C.

¹H-NMR(CDCl₃): 1.21 (3H, t, J=7.5 Hz), 2.44 (6H, s), 2.65-2.78 (2H, m), 2.94-3.23 (3H, m), 4.12-4.18 (1H, m), 4.54-4.59 (1H, m), 6.90 (1H, d, J=8.4 Hz), 6.94-6.96 (1H, m), 6.97 (1H, d, J=8.4 Hz), 7.96 (1H, br s).

EXAMPLE 30

(5-Bromo-2-triisopropylsilanyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)dimethyl-amine (42)

Compound (19-16) 2.00 g was added to a suspension of 60% sodium hydride 300.8 mg in tetrahydrofuran 30 ml with coolingin ice. The mixture was stirred for 1 h. Then, triisopropylsilyl chloride (TIPSCl) 1.6 ml was added with cooling in ice. The mixture was stirred for 4 h with cooling in ice. Water was added to reaction mixture with cooling in ice. The mixture was extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in ethyl acetate:hexane (1:4) to give a pale brown oil 2.67 g. This was recrystallized from isopropyl ether to give colorless crystals, m.p. 119-121° C. 1.85 g. Yield 60%

¹H-NMR(CDCl₃): 1.13 (18H, dd, J=7.5, 0.9 Hz), 1.58-1.72 (3H, m), 2.45 (6H, s), 3.03-3.26 (3H, m), 4.18-4.24 (1H, m), 4.66 (1H, dd, J=12.3, 1.5 Hz), 6.96 (1H; d, J=8.7 Hz), 7.00 (1H, s), 7.20 (1H, d, J=8.7 Hz).

EXAMPLE 31

(5-Fluoro-2-triisopropylsilanyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)dimethyl-amine (43)

A solution of compound (42) 451 mg in dry tetrahydrofuran 5 ml was cooled at −70° C. n-BuLi (1.56 mol 11 hexane solution) 1.3 ml was added dropwise to the mixture, which was stirred for 1 h. Then, N-fluorobenzenesulfonimide 694 mg was added and the mixture was stirred for 3.5 h. The reaction mixtures was diluted with an aqueous ammonium chloride solution, extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in ethyl acetate:hexane (1:5) to give a yellow oil. This was chromatographed on thin aluminum oxide plates (Merck precoated TLC plate alumina 60F254 in ethyl acetate:hexane (1:5)) to give the titled compound as a pale yellow oil, 100 mg.

¹H-NMR(CDCl₃): 1.28 (18H, dd, J=7.5, 0.9 Hz), 1.58-1.70 (3H, m), 2.45 (6H, s), 2.95-3.28 (3H, m), 4.20-4.26 (1H, m), 4.62 (1H, dd, J=11.7, 1.2 Hz), 6.86-6.97 (2H, m), 7.03 (1H, s).

EXAMPLE 32

Dimethyl-(5-methylsulfanyl-2-triisopropylsilanyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]-azulen-8-yl)amine (44)

A solution of compound (42) 451 mg in dry tetrahydrofuran 5 ml was cooled at −70° C. n-BuLi (1.56 mol/l hexane solution) 1.3 ml was added dropwise to the solution and the mixture was stirred for 1 h. Then, dimethyldisulfide 185 μl was added and the mixture was stirred for 2 h. The reaction mixtures was diluted with an aqueous ammonium chloride solution and extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in ethyl acetate:hexane (1:5) to give the titled compound as colorless crystals, 289.8 mg. Yield 69%. This was recrystallized from hexane to give the titled compound as colorless crystals, m.p. 77-79° C.

¹H-NMR(CDCl₃): 1.13 (18H, d, J=7.5 Hz), 1.58-1.74 (3H, m), 2.45 (total 9H, each s), 2.97-3.30 (3H, m), 4.22 (1H, d, J=12.0, 6.3 Hz), 4.68 (1H, dd, J=12.0, 1.2 Hz), 6.99 (1H, s), 7.04 (1H, d, J=8.4 Hz), 7.10 (1H, d, J=8.7 Hz).

EXAMPLE 33

8-Dimethylamino-2-triisopropylsilanyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]-azulene-5-carbaldehyde (45)

A solution of compound (42) 750 mg in dry tetrahydrofuran 7 ml was cooled at −70° C. and n-BuLi (1.56 mol/l hexane solution) 2.2 ml was added dropwise to the solution. The mixture was stirred for 1 h. Dimethylformamide 257 μL was added and the mixture was stirred for 2 h. The reaction mixtures was diluted with an aqueous ammonium chloride solution and extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in ethyl acetate:hexane (1:4) to give the titled compound as yellow oil, 556 mg. This was recrystallized from hexane to give the titled compound as colorless crystals, m.p. 104-106° C., 395 mg. Yield 59%

¹H-NMR(CDCl₃): 1.14 (18H, d, J=7.5 Hz), 1.55-1.72 (3H, m), 2.45 (6H, s), 2.97-3.30 (3H, m), 4.29 (1H, dd, J=12.6, 6.3 Hz), 4.65 (1H, d, J=12.6 Hz), 7.04 (1H, s), 7.07 (1H, d, J=9.0 Hz), 7.60 (1H, d, J=8.7 Hz), 10.50 (1H, s).

EXAMPLE 34

8-Dimethylamino-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]-azulene-5-carbaldehyde (46-1)

(R₁₁=CHO)

Tetra-n-butylammoniumfluoride (1 mol/1 tetrahydrofuran solution) 2.2 ml was added to compound (45) 496 mg in tetrahydrofuran 10 ml with cooling in ice. The mixture was stirred for 3 h, diluted with water and ethyl acetate and, extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in ethyl acetate:hexane (2:1) to give colorless crystals, 273.2 mg. This was recrystallized from acetone-isopropyl ether to give the titled compound as colorless crystals, m.p.175-176° C., 265 4 m g. Yield 88%.

¹H-NMR(DMSO-d₆): 2.29 (6H, s), 2.78-3.13 (3H, m), 4.31 (1H, dd, J=12.3, 6.6 Hz), 4.58 (1H, d, J=12.3 Hz), 6.99 (1H, dd, J=8.4, 0.9 Hz), 7.23 (1H, s), 7.40 (1H, d, J=8.4 Hz), 10.36 (1H, d, J=0.9 Hz), 11.48 (1H, br s).

Following compounds were obtained, according to the similar treatment. Compd No R¹¹ m.p. (° C.) ¹H-NMR(CDCl₃) 46-2 F 148-150 2.44(6H, s), 2.93-3.25(3H, m), 4.24(1H, dd, J=12.3, 6.6Hz), 4.63(1H, dd, J=12.3, 1.2Hz), 6.83(1H, dd, J=8.7, 3.6Hz), 6.97(1H, dd, J=11.4, 8.7Hz), 7.01(1H, m), 8.04(1H, br s) 46-3 SMe 112-113 2.44(3H, s), 2.44(6H, s), 2.97-3.24(3H, m), 4.24(1H, dd, J=12.3, 6.3Hz), 4.69(1H, dd, J=12.3, 2.1Hz), 6.94(1H, d, J=8.4Hz), 6.97-6.99(1H, m), 7.19(1H, d, J=8.7Hz), 8.09(1H, br s) (Scheme of Reactions, Examples 35-37)

EXAMPLE 35

8-Dimethylamino-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]-azulene-5-carbaldehyde oxime (47)

Hydroxylamine hydrogenchloride 83.4 mg and sodium acetate 98.4 mg were added to a suspension of compound (46-1) 244 mg in 95% ethanol 10 ml. The mixture was stirred at room temperature for 2 h and concentrated under reduced pressure. Water was added to the residue, which was made alkaline with an aqueous saturated sodium hydrogencarbonate solution. Colorless precipitates appeared and were collected by filtration, washed with methanol-ethyl acetate to give the titled compound as colorless crystals, m.p. 230-235° C. (dec.), 228 mg. Yield 88%.

¹H-NMR(DMSO-d₆): 2.28 (6H, s), 2.73-3.12 (3H, m), 4.15 (1H, dd, J=12.0, 6.6 Hz), 4.49 (1H, d, J=12.3 Hz), 6.93 (1H, d, J=7.8 Hz), 7.13 (1H, br d, J=2.7 Hz), 7.38 (1H, d, J=8.7 Hz), 8.39 (1H, s), 10.66 (1H, s), 11.12 (1H, br s).

EXAMPLE 36

8-Dimethylamino-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]-azulene-5-carbonitrile (48) Triethylamine 33 μl and trichloroacetyl chloride 13 μl were added to a solution of compound (47) 28.9 mg in dichloromethane 2 ml with cooling ice and the mixture was stirred with cooling in ice and at room temperature for 18 h. A saturated sodium hydrogencarbonate solution was added thereto for alkalinization. The mixture was extracted with chloroform. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in chloroform:methanol (97:3) to give the titled compound 26.3 mg as colorless crystals. Yield 98%. Furthermore, the titled compound was recrystallized from methanol-isopropyl ether to give colorless crystals, m.p. 205-207° C.

¹H-NMR(CD₃OD): 2.41 (6H, s), 2.89-3.23 (3H, m), 4.39 (1H, dd, J=12.6, 6.9 Hz), 4.64 (1H, d, J=12.6 Hz), 7.03 (1H, d, J=8.7 Hz), 7.17 (1H, d, J=8.7 Hz), 7.18 (1H, m).

EXAMPLE 37

8-Dimethylamino-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulene-5-carboxylic acid amide (49)

Polyphophoric acid 420 mg was added to compound (48) 31.6 mg under an argon atmosphere and the mixture was heated at 90° C. for 6 h. Ice-water was added to the reaction mixture, which was made alkaline with an aqueous 5 N-sodium hydroxide solution and extracted with chloroform. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in chloroform:methanol (97:3) to give the titled compound as colorless crystals, 20.9 mg. Yield 62%. Furthermore, the titled compound was recrystallized from acetone-isopropyl ether to give colorless crystals, m.p. 182-183° C.

¹H-NMR(DMSO-d₆): 2.29 (6H, s), 2.76-3.13 (3H, m), 4.24 (1H, dd, J=12.0, 6.0 Hz), 4.64 (1H, d, J=12.3 Hz), 6.97 (1H, d, J=8.7 Hz), 7.18 (1H, d, J=2.1 Hz), 7.22 (1H, br s), 7.66 (1H, d, J=8.7 Hz), 7.68(1H, br s), 11.20 (1H, br s) (Scheme of Reactions, Examples 38-40)

EXAMPLE 38

N-Cyclopropyl-2,2,2-trifluoromethyl-N-(2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)acetamide (50)

Compound (19-19) 355 mg was dissolved in dry tetrahydrofuran 11 ml. A solution of triethylamine 178 mg and trifluoroacetic anhydride 344 mg in dry tetrahydrofuran 0.5 ml was added to the solution with cooling in ice. The mixture was stirred with cooling in ice for 2 h. Triethylamine 78 mg and trifluoroacetic anhydride 156 mg in dry tetrahydrofuran 0.2 ml were again added. The mixture was stirred with cooling in ice for 2 h and concentrated under reduced pressure. Water was added to the residue, which was extracted with ether. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide 15 g in chloroform: hexane (4:1) to give the titled compound as pale yellow crystals, 415 mg (yield 82%), m.p. 49-53° C.

¹H-NMR(CDCl₃): 0.94-1.06 (4H, m), 3.04-3.14 (2H, m), 3.64-3.74 (1H, m), 4.10-4.15 (1H, m), 4.46 (1H, dd, J=12.6, 1.8 Hz), 4.70 (1H, dd, J=12.6, 6.6 Hz), 6.64 (1H, dd, J=7.5, 1.2 Hz), 6.97 (1H, s), 7.00 (1H, dd, J=8.1, 1.2 Hz), 7.08 (1H, d, J=8.1 Hz), 8.17 (1H, br s)

EXAMPLE 39

N-(2-Benzenesulfonyl-2,7,8,9-tetrahydro-6-oxo-2-aza-benzo [cd]azulen-8-yl)-N-cyclopropyl-2,2,2,-trifluoroacetamide (51)

60% Sodium hydride 56 mg was added to a solution of compound (50) 324 mg in dimethylformamide 12 ml with cooling in ice and the mixture was stirred at room for 1 h. Benzenesulfonyl chloride 238 mg was added dropwise with cooling in ice and then, the mixture was stirred at 40° C. for 21 h. Ice-water and then an aqueous sodium hydrogencarbonate solution were added to the reaction mixture, which was extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in chloroform hexane (1:2) to give the titled compound as a colorless oil, 130 mg (yield 28%).

¹H-NMR(CDCl₃): 0.88-1.05 (4H, m), 3.03-3.09 (2H, m), 3.58-3.68 (1H, m), 3.99-4.06 (1H, m), 4.40 (1H, dd, J=12.9, 1.5 Hz), 4.59 (1H, dd, J=12.9, 6.3 Hz), 6.77 (1H, dd, J=7.8, 0.6 Hz), 7.20 (1H, t, J=8.1 Hz), 7.34 (1H, s), 7.44-7.66 (4H, m), 7.86-7.90 (2H, m)

EXAMPLE 40

(2-Benzenesulfonyl-2,7,8,9-tetrahydro-6-oxo-2-aza-benzo[cd]azulen-8-yl)cyclopropylamine (52)

Compound (51) 129 mg was dissolved in ethanol 3 ml. Sodium hydrogenborohydride 42 mg was added to the solution at room temperature and the mixture was stirred for 23 h. Water was added with cooling in ice to the reaction mixture, which was extracted with chloroform. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in chloroform:hexane (1:1) to give the titled compound as a colorless oil, 98 mg. Yield 96%. The titled compound was treated with 1 eq. of oxalic acid to give the salt, which was recrystallized from isopropanol-ether to give colorless crystals, m.p. 119-122° C. (dec.).

¹H-NMR(CDCl₃): 0.30-0.49 (4H, m), 2.21-2.27 (1H, m), 2.94-3.12 (2H, m), 3.31-3.37 (1H, m), 4.29-4.31 (2H, m), 6.77 (1H, d, J=7.8 Hz), 7.1.9 (1H, t, J=8.1 Hz), 7.33 (1H, s), 7.42-7.63 (4H, m), 7.86-7.90 (2H, m) (Scheme of Reactions, Examples 41-44)

EXAMPLE 41

(2-Benzenesulfonyl-1-iodo-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)dimethylamine (53)

LDA was prepared by addition of n-BuLi (1.56 mol/l hexane solution) 1.08 ml to a solution of diisopropylamine 255 μl in dry tetrahydrofuran 3 ml at −70° C. Then, a solution of compound (20-1) 500 mg in dry tetrahydrofuran 2 ml was added at that temperature to the mixture, which was stirred for 2 h. Then, a solution of iodine 426 mg in dry tetrahydrofuran 2 ml was added and the mixture was stirred for 2 h. Ice was added to the reaction mixtures, which was extracted with chloroform. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in ethyl acetate hexane (1:5) to give the titled compound as colorless crystals 514 mg. Yield 76%. This was recrystallized from from acetone-isopropyl ether to give colorless crystals, m.p. 136-137° C.

¹H-NMR(CDCl₃): 2.36 (6H, s), 2.87-2.97 (3H, m), 4.08-4.14 (1H, m), 4.41 (1H, d, J=12.6 Hz), 6.75 (1H, d, J=7.5 Hz), 7.40-7.45 (2H, m), 7.53-7.58 (1H, m), 7.86-7.90 (2H, m), 7.96 (1H, d, J=7.8 Hz).

EXAMPLE 42

(2-Benzenesulfonyl-1-vinyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)dimethylamine (54)

Tri-n-butyl(vinyl)tin 484.4 mg, tetrakis(triphenylphosphine)palladium 690 mg and lithium chloride 127.7 mg were added to a solution of compound (53) 491 mg in dry dimethylformamide 10 ml under nitrogen atmosphere. The mixture was heated at 100° C. for 3 h, diluted with ethyl acetate after cooling and filtered through cerite to remove the insoluble materials. The filtrate was washed with an aqueous saturated sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was pulverized in hexane, collected by filtration and chromatographed on aluminum oxide in chloroform: hexane (1:1) to give the titled compound as colorless crystals 602.2 mg. Yield 79%. Furthermore, the titled compound was recrystallized from acetone-isopropyl ether to give colorless crystals, m.p. 133-134° C.

¹H-NMR(CDCl₁): 2.53 (6H, s), 2.78-3.10 (3H, m), 4.11 (1H, dd, J=12.6, 6.6 Hz), 4.41 (1H, d, J=12.6 Hz), 5.36 (1H, dd, J=17.7, 1.5 Hz), 5.69 (1H, dd, J=11.4, 1.5 Hz), 6.77 (1H, dd, J=8.1, 0.9 Hz), 7.18 (1H, dd, J=18.0, 11.4 Hz), 7.19 (1H, t, J=8.1 Hz), 7.34-7.53 (3H, m), 7.73-7.76 (2H, m), 7.87 (1H, dd, J=8.4, 0.9 Hz).

EXAMPLE 43

(2-Benzenesulfonyl-1-ethyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)dimethylamine (55)

Compound (54) 200.1 mg was dissolved in a mixture of methanol 8 ml and tetrahydrofuran 4 ml. 10% Pd/C 49.8 mg was added. The mixture was stirred under hydrogen atmosphere for 18 h at room temperature. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in chloroform:hexane (1:1) to give the titled compound as a colorless oil 198 mg. Yield 0.98%. This was treated with 1 eq. of oxalic acid to give the salt, which was recrystallized from ether-methanol to give colorless crystals, m.p. 193-194° C. (dec.).

¹H-NMR(CDCl₃): 1.28 (3H, t, J=7.5 Hz), 2.41 (6H, s), 2.89-3.07 (5H, m), 4.07-4.13 (1H, m), 4.43 (1H, d, J=12.6 Hz), 6.75 (1H, dd, J=7.8, 0.9 Hz), 7.13 (1H, t, J=8.1 Hz), 7.37-7.43 (2H, m), 7.49-7.54 (1H, m), 7.71-7.75 (2H, m), 7.83 (1H, dd, J=8.1, 0.9 Hz).

EXAMPLE 44

(1-Ethyl-2,7,8,9-tetrahydro-6-oxa-2-azabenzo[cd]azulen-8-yl)dimethylamine (56-1)

Magnesium (turning) 246 mg was added to compound (55) in methanol 9 ml and the mixture was stirred at room temperature for 3 h. Ice was added to the reaction mixture which was diluted with chloroform. The insoluble materials were filtered off through cerite and the filtrate was extracted with chloroform. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in chloroform:hexane (2:1) to give the titled compound as a pale yellow oil 97.8 mg. Yield 79%. This was treated with 1 eq. oxalic acid to give the salt, which was recrystallized from ether-methanol to give colorless crystals, m.p. 236-237° C. (dec.).

¹H-NMR(CDCl₃): 1.29 (3H, t, J=7.5 Hz), 2.45 (6H, s), 2.75 (2H, q, J=7.5 Hz), 2.86-3.13 (3H, m), 4.12 (1H, dd, J=12.3, 6.3 Hz), 4.54 (1H, d, J=12.3 Hz), 6.59 (1H, dd, J=7.5, 0.9 Hz), 6.91 (1H, dd, J=8.1, 0.9 Hz), 6.99 (1H, t, J=7.8 Hz), 7.90 (1H, br s). Following compounds were obtained, according to the similar treatment. Compd No R⁷ m.p. ¹H-NMR(CDCl₃) 56-2 vinyl 195-198 2.43(6H, s), 2.64-3.25(3H, m), (dec.) 4.12(1H, dd, J=12.0, 6.3Hz), 4.54(1H, dd, oxalate J=12.0, 2.1Hz), 5.27(1H, d, J=11.4Hz), 5.43(1H, d, J=11.4Hz), 6.58(1H, dd, J=7.8, 0.9Hz), 6.79(1H, dd, J=17.7, 11.4Hz), 6.91(1H, dd, J=8.1, 0.9Hz), 7.06(1H, t, J=8.1Hz), 8.11(1H, br s),

EXAMPLE 45

N-(2,7,8,9-Tetrahydro-6-oxo-2-azabenzo[cd]azulen-8-yl)hydrazinecarboxylic acid tert-butyl ester (57)

t-Butylbuthoxycarbonyl hydrazide 139 mg was added to a solution of compound (18-1) 170 mg in dry tetrahydrofuran 6 ml. The mixture was stirred at room temperature for 4 h and concentrated under reduced pressure. Trifluoroacetic acid 0.7 ml and triethylsilane 212 mg were added to the residue. The mixture was stirred for 80 min. 1N-HCl and then potassium hydroxide pellets were added to the reaction mixture with cooling in ice to alkaline. The mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in chloroform:hexane (4:1) to give the titled compound as crystals, 158 mg (yield 58%). The crude crystalline materials were recrystallized from hexane-ethyl acetate to give pale yellow crystals, m.p. 171-173° C. (dec.).

¹H-NMR(CDCl₃): 1.46 (9H, s), 2.84-2.93 (1H, m), 3.17-3.24 (2H, m), 3.59-3.66 (1H, m), 4.23 (1H, dd, J=12.3, 7.2 Hz), 4.37 (1H, d, J=12.3 Hz), 6.21 (1H, br s), 6.61 (1H, d, J=7.5 Hz), 6.96-7.08 (3H, m), 8.11 (1H, br s)

EXAMPLE A

As examples of a compound (I), compounds (I-a) and compounds (I-b) were shown in Table 7-28 and Table 29-42, respectively. TABLE 7 (I-a)

Compd No R⁴ R⁷ R⁸ 1 COOH H H 2 COOMe H H 3 COOEt H H 4 COO-tBu H H 5 CONH₂ H H 6 CONHMe H H 7 CONHEt H H 8 CONH-nPr H H 9 CONMe₂ H H 10 CONEt₂ H H 11 CON(nPr)₂ H H 12 CONHPh H H 13

H H 14

H H 15

H H 16 NH₂ H H 17 NHMe H H 18 NHEt H H 19 NH-nPr H H 20 NMe₂ H H 21 NEt₂ H H 22 N(nPr)₂ H H 23

H H 24

H H 25

H H 26 NHCOMe H H 27 NHCOEt H H

TABLE 8 Compd No R⁴ R⁷ R⁸ 1 NHCO-nPr H H 2 NHCOPh H H 3 NMeCOMe H H 4 N(nPr)COMe H H 5 NMeCOPh H H 6 N(nPr)COPh H H 7 NHCOOMe H H 8 NHCOOEt H H 9 NHCOO-tBu H H 10 NHCOOCH₂Ph H H 11 NMeCOOMe H H 12 N(nPr)COOMe H H 13 NMeCOOCH₂Ph H H 14 N(nPr)COOCH₂Ph H H 15 NHSO₂Me H H 16 NHSO₂Et H H 17 NHSO₂Ph H H 18 NHTs H H 19 NMeSO₂Me H H 20 N(nPr)SO₂Me H H 21 NMeSO₂Ph H H 22 N(nPr)SO₂Ph H H 23 COOH Me H 24 COOMe Me H 25 COOEt Et H 26 COO-tBu nPr H 27 CONH₂ Me H 28 CONHMe Me H 29 CONHEt Et H 30 CONH-nPr nPr H 31 CONMe₂ Me H 32 CONEt₂ Et H 33 CON(nPr)₂ nPr H 34 CONHPh Me H 35

Me H 36

Et H 37

nPr H 38 NH₂ Me H 39 NHMe Me H 40 NHEt Et H

TABLE 9 Compd No R⁴ R⁷ R⁸ 1 NH-nPr nPr H 2 NMe₂ Me H 3 NEt₂ Et H 4 N(nPr)₂ nPr H 5

Me H 6

Et H 7

nPr H 8 NHCOMe Me H 9 NHCOEt Et H 10 NHCO-nPr nPr H 11 NHCOPh Me H 12 NMeCOMe Me H 13 N(nPr)COMe Et H 14 NMeCOPh nPr H 15 N(nPr)COPh Me H 16 NHCOOMe Me H 17 NHCOOEt Et H 18 NHCOO-tBu nPr H 19 NHCOOCH₂Ph Me H 20 NMeCOOMe nPr H 21 N(nPr)COOMe nPr H 22 NMeCOOCH₂Ph Me H 23 N(nPr)COOCH₂Ph nPr H 24 NHSO₂Me Me H 25 NHSO₂Et Et H 26 NHSO₂Ph nPr H 27 NHTs Et H 28 NMeSO₂Me Me H 29 N(nPr)SO₂Me nPr H 30 NMeSO₂Ph Me H 31 N(nPr)SO₂Ph Me H 32 COOH Br H 33 COOMe Br H 34 COOEt CN H 35 COO-tBu Br H 36 CONH₂ Br H 37 CONHMe Br H 38 CONHEt CN H 39 CONH-nPr Br H 40 CONMe₂ Br H 41 CONEt₂ CN H 42 CON(nPr)₂ Br H

TABLE 10 Compd No R⁴ R⁷ R⁸ 1 CONHPh CN H 2

Br H 3

Br H 4

CN H 5 NH₂ Br H 6 NHMe Br H 7 NHEt CN H 8 NH-nPr Br H 9 NMe₂ Br H 10 NEt₂ CN H 11 N(nPr)₂ Br H 12

Br H 13

CN H 14

Br H 15 NHCOMe Br H 16 NHCOEt Br H 17 NHCO-nPr CN H 18 NHCOPh Br H 19 NMeCOMe Br H 20 N(nPr)COMe Br H 21 NMeCOPh CN H 22 N(nPr)COPh Br H 23 NHCOOMe Br H 24 NHCOOEt CN H 25 NHCOO-tBu Br H 26 NHCOOCH₂Ph Br H 27 NMeCOOMe CN H 28 N(nPr)COOMe Br H 29 NMeCOOCH₂Ph Br H 30 N(nPr)COOCH₂Ph CN H 31 NHSO₂Me Br H 32 NHSO₂Et Br H 33 NHSO₂Ph Br H 34 NHTs CN H 35 NMeSO₂Me Br H 36 N(nPr)SO₂Me Br H 37 NMeSO₂Ph Br H 38 N(nPr)SO₂Ph CN H 39 COOH Ph H

TABLE 11 Compd No R⁴ R⁷ R⁸ 1 COOMe Ph H 2 COOEt Ph H 3 COO-tBu Ph H 4 CONH₂ Ph H 5 CONHMe Ph H 6 CONHEt Ph H 7 CONH-nPr Ph H 8 CONMe₂ Ph H 9 CONEt₂ Ph H 10 CON(nPr)₂ Ph H 11 CONHPh Ph H 12

Ph H 13

Ph H 14

Ph H 15 NH₂ Ph H 16 NHMe Ph H 17 NHEt Ph H 18 NH-nPr Ph H 19 NMe₂ Ph H 20 NEt₂ Ph H 21 N(nPr)₂ Ph H 22

Ph H 23

Ph H 24

Ph H 25 NHCOMe Ph H 26 NHCOEt Ph H 27 NHCO-nPr Ph H 28 NHCOPh Ph H 29 NMeCOMe Ph H 30 N(nPr)COMe Ph H 31 NMeCOPh Ph H 32 N(nPr)COPh Ph H 33 NHCOOMe Ph H 34 NHCOOEt Ph H 35 NHCOO-tBu Ph H 36 NHCOOCH₂Ph Ph H 37 NMeCOOMe Ph H 38 N(nPr)COOMe Ph H

TABLE 12 Compd No R⁴ R⁷ R⁸ 1 NMeCOOCH₂Ph Ph H 2 N(nPr)COOCH₂Ph Ph H 3 NHSO₂Me Ph H 4 NHSO₂Et Ph H 5 NHSO₂Ph Ph H 6 NHTs Ph H 7 NMeSO₂Me Ph H 8 N(nPr)SO₂Me Ph H 9 NMeSO₂Ph Ph H 10 N(nPr)SO₂Ph Ph H 11 COOH H Me 12 COOMe H Me 13 COOEt H Me 14 COO-tBu H Me 15 CONH₂ H Me 16 CONHMe H Me 17 CONHEt H Me 18 CONH-nPr H Me 19 CONMe₂ H Me 20 CONEt₂ H Me 21 CON(nPr)₂ H Me 22 CONHPh H Me 23

H Me 24

H Me 25

H Me 26 NH₂ H Me 27 NHMe H Me 28 NHEt H Me 29 NH-nPr H Me 30 NMe₂ H Me 31 NEt₂ H Me 32 N(nPr)₂ H Me 33

H Me 34

H Me 35

H Me 36 NHCOMe H Me 37 NHCOEt H Me

TABLE 13 Compd No R4 R7 R8 1 NHCO-nPr H Me 2 NHCOPh H Me 3 NMeCOMe H Me 4 N(nPr)COMe H Me 5 NMeCOPh H Me 6 N(nPr)COPh H Me 7 NHCOOMe H Me 8 NHCOOEt H Me 9 NHCOO-tBu H Me 10 NHCOOCH₂Ph H Me 11 NMeCOOMe H Me 12 N(nPr)COOMe H Me 13 NMeCOOCH₂Ph H Me 14 N(nPr)COOCH₂Ph H Me 15 NHSO₂Me H Me 16 NHSO₂Et H Me 17 NHSO₂Ph H Me 18 NHTs H Me 19 NMeSO₂Me H Me 20 N(nPr)SO₂Me H Me 21 NMeSO₂Ph H Me 22 N(nPr)SO₂Ph H Me 23 COOH Me Me 24 COOMe Me Me 25 COOEt Et Me 26 COO-tBu Me Me 27 CONH₂ nPr Me 28 CONHMe Me Me 29 CONHEt Et Me 30 CONH-nPr nPr Me 31 CONMe₂ Me Me 32 CONEt₂ Et Me 33 CON(nPr)₂ nPr Me 34 CONHPh Me Me 35

Me Me 36

Et Me 37

nPr Me

TABLE 14 Compd No R⁴ R⁷ R⁸ 1 NH₂ Me Me 2 NHMe Me Me 3 NHEt Me Me 4 NH-nPr Et Me 5 NMe₂ Me Me 6 NEt₂ nPr Me 7 N(nPr)₂ nPr Me 8

Me Me 9

Et Me 10

Me Me 11 NHCOMe nPr Me 12 NHCOEt Me Me 13 NHCO-nPr Et Me 14 NHCOPh Me Me 15 NMeCOMe nPr Me 16 N(nPr)COMe Me Me 17 NMeCOPh Et Me 18 N(nPr)COPh Me Me 19 NHCOOMe nPr Me 20 NHCOOEt Me Me 21 NHCOO-tBu Et Me 22 NHCOOCH₂Ph Me Me 23 NMeCOOMe nPr Me 24 N(nPr)COOMe Me Me 25 NMeCOOCH₂Ph nPr Me 26 N(nPr)COOCH₂Ph Me Me 27 NHSO₂Me Et Me 28 NHSO₂Et nPr Me 29 NHSO₂Ph Me Me 30 NHTs nPr Me 31 NMeSO₂Me Me Me 32 N(nPr)SO₂Me Et Me 33 NMeSO₂Ph Me Me 34 N(nPr)SO₂Ph Et Me 35 COOH Br Me 36 COOMe Br Me 37 COOEt CN Me 38 COO-tBu CN Me

TABLE 15 Compd No R⁴ R⁷ R⁸ 1 CONH₂ Br Me 2 CONHMe Br Me 3 CONHEt CN Me 4 CONH-nPr Br Me 5 CONMe₂ Br Me 6 CONEt₂ CN Me 7 CON(nPr)₂ Br Me 8 CONHPh CN Me 9

Br Me 10

CN Me 11

Br Me 12 NH₂ Br Me 13 NHMe CN Me 14 NHEt CN Me 15 NH-nPr Br Me 16 NMe₂ Br Me 17 NEt₂ CN Me 18 N(nPr)₂ Br Me 19

Br Me 20

CN Me 21

Br Me 22 NHCOMe Br Me 23 NHCOEt Br Me 24 NHCO-nPr CN Me 25 NHCOPh Br Me 26 NMeCOMe Br Me 27 N(nPr)COMe 6N Me 28 NMeCOPh Br Me 29 N(nPr)COPh Br Me 30 NHCOOMe CN Me 31 NHCOOEt Br Me 32 NHCOO-tBu Br Me 33 NHCOOCH₂Ph Br Me 34 NMeCOOMe CN Me 35 N(nPr)COOMe Br Me

TABLE 16 Compd No R⁴ R⁷ R⁸ 1 NMeCOOCH₂Ph Br Me 2 N(nPr)COOCH₂Ph CN Me 3 NHSO₂Me Br Me 4 NHSO₂Et Br Me 5 NHSO₂Ph CN Me 6 NHTs Br Me 7 NMeSO₂Me Br Me 8 N(nPr)SO₂Me CN Me 9 NMeSO₂Ph Br Me 10 N(nPr)SO₂Ph Br Me 11 COOH Ph Me 12 COOMe Ph Me 13 COOEt Ph Me 14 COO-tBu Ph Me 15 CONH₂ Ph Me 16 CONHMe Ph Me 17 CONHEt Ph Me 18 CONH-nPr Ph Me 19 CONMe₂ Ph Me 20 CONEt₂ Ph Me 21 CON(nPr)₂ Ph Me 22 CONHPh Ph Me 23

Ph Me 24

Ph Me 25

Ph Me 26 NH₂ Ph Me 27 NHMe Ph Me 28 NHEt Ph Me 29 NH-nPr Ph Me 30 NMe₂ Ph Me 31 NEt₂ Ph Me 32 N(nPr)₂ Ph Me 33

Ph Me 34

Ph Me 35

Ph Me

TABLE 17 Compd No R⁴ R⁷ R⁸ 1 NHCOMe Ph Me 2 NHCOEt Ph Me 3 NHCO-nPr Ph Me 4 NHCOPh Ph Me 5 NMeCOMe Ph Me 6 N(nPr)COMe Ph Me 7 NMeCOPh Ph Me 8 N(nPr)COPh Ph Me 9 NHCOOMe Ph Me 10 NHCOOEt Ph Me 11 NHCOOtBu Ph Me 12 NHCOOCH₂Ph Ph Me 13 NMeCOOMe Ph Me 14 N(nPr)COOMe Ph Me 15 NMeCOOCH₂Ph Ph Me 16 N(nPr)COOCH₂Ph Ph Me 17 NHSO₂Me Ph Me 18 NHSO₂Et Ph Me 19 NHSO₂Ph Ph Me 20 NHTs Ph Me 21 NMeSO₂Me Ph Me 22 N(nPr)SO₂Me Ph Me 23 NMeSO₂Ph Ph Me 24 N(nPr)SO₂Ph Ph Me 25 COOH H COPh 26 COOMe H COPh 27 COOEt H COPh 28 COO-tBu H COPh 29 CONH₂ H COPh 30 CONHMe H COPh 31 CONHEt H COPh 32 CONH-nPr H COPh 33 CONMe₂ H COPh 34 CONEt₂ H COPh 35 CON(nPr)₂ H COPh 36 CONHPh H COPh 37

H COPh 38

H COPh 39

H COPh

TABLE 18 Compd No R⁴ R⁷ R⁸ 1 NH₂ H COPh 2 NHMe H COPh 3 NHEt H COPh 4 NH-nPr H COPh 5 NMe₂ H COPh 6 NEt₂ H COPh 7 N(nPr)₂ H COPh 8

H COPh 9

H COPh 10

H COPh 11 NHCOMe H COPh 12 NHCOEt H COPh 13 NHCO-nPr H COPh 14 NHCOPh H COPh 15 NMeCOMe H COPh 16 N(nPr)COMe H COPh 17 NMeCOPh H COPh 18 N(nPr)COPh H COPh 19 NHCOOMe H COPh 20 NHCOOEt H COPh 21 NHCOO-tBu H COPh 22 NHCOOCH₂Ph H COPh 23 NMeCOOMe H COPh 24 N(nPr)COOMe H COPh 25 NMeCOOCH₂Ph H COPh 26 N(nPr)COOCH₂Ph H COPh 27 NHSO₂Me H COPh 28 NHSO₂Et H COPh 29 NHSO₂Ph H COPh 30 NHTs H COPh 31 NMeSO₂Me H COPh 32 N(nPr)SO₂Me H COPh 33 NMeSO₂Ph H COPh 34 N(nPr)SO₂Ph H COPh 35 COOH Me COPh 36 COOMe Me COPh 37 COOEt Et COPh 38 COO-tBu nPr COPh 39 CONH₂ Me COPh

TABLE 19 Compd No R⁴ R⁷ R⁸ 1 CONHMe Et COPh 2 CONHEt nPr COPh 3 CONH-nPr Me COPh 4 CONMe₂ Et COPh 5 CONEt₂ nPr COPh 6 CON(nPr)₂ nPr COPh 7 CONHPh Me COPh 8

nPr COPh 9

Et COPh 10

Me COPh 11 NH₂ Et COPh 12 NHMe Me COPh 13 NHEt Et COPh 14 NH-nPr nPr COPh 15 NMe₂ Me COPh 16 NEt₂ Et COPh 17 N(nPr)₂ nPr COPh 18

Me COPh 19

Me COPh 20

Me COPh 21 NHCOMe Et COPh 22 NHCOEt Et COPh 23 NHCO-nPr Et COPh 24 NHCOPh nPr COPh 25 NMeCOMe nPr COPh 26 N(nPr)COMe nPr COPh 27 NMeCOPh Et COPh 28 N(nPr)COPh Et COPh 29 NHCOOMe Et COPh 30 NHCOOEt Me COPh 31 NHCOO-tBu Me COPh 32 NHCOOCH₂Ph Me COPh 33 NMeCOOMe Et COPh 34 N(nPr)COOMe nPr COPh 35 NMeCOOCH₂Ph nPr COPh 36 N(nPr)COOCH₂Ph nPr COPh 37 NHSO₂Me Me COPh 38 NHSO₂Et Et COPh

TABLE 20 Compd No R⁴ R⁷ R⁸ 1 NHSO₂Ph nPr COPh 2 NHTs Me COPh 3 NMeSO₂Me Et COPh 4 N(nPr)SO₂Me nPr COPh 5 NMeSO₂Ph Me COPh 6 N(nPr)SO₂Ph Me COPh 7 COOH Br COPh 8 COOMe Br COPh 9 COOEt CN COPh 10 COO-tBu Br COPh 11 CONH₂ CN COPh 12 CONHMe Br COPh 13 CONHEt CN COPh 14 CONH-nPr Br COPh 15 CONMe₂ Br COPh 16 CONEt₂ CN COPh 17 CON(nPr)₂ Br COPh 18 CONHPh Br COPh 19

CN COPh 20

Br COPh 21

Br COPh 22 NH₂ CN COPh 23 NHMe Br COPh 24 NHEt CN COPh 25 NH-nPr Br COPh 26 NMe₂ Br COPh 27 NEt₂ Br COPh 28 N(nPr)₂ CN COPh 29

Br COPh 30

Br COPh 31

CN COPh 32 NHCOMe Br COPh 33 NHCOEt CN COPh 34 NHCO-nPr Br COPh 35 NHCOPh CN COPh 36 NMeCOMe Br COPh 37 N(nPr)COMe CN COPh

TABLE 21 Compd No R⁴ R⁷ R⁸ 1 NMeCOPh CN COPh 2 N(nPr)COPh Br COPh 3 NHCOOMe Br COPh 4 NHCOOEt CN COPh 5 NHCOO-tBu Br COPh 6 NHCOOCH₂Ph Br COPh 7 NMeCOOMe CN COPh 8 N(nPr)COOMe Br COPh 9 NMeCOOCH₂Ph Br COPh 10 N(nPr)COOCH₂Ph CN COPh 11 NHSO₂Me Br COPh 12 NHSO₂Et Br COPh 13 NHSO₂Ph CN COPh 14 NHTs Br COPh 15 NMeSO₂Me Br COPh 16 N(nPr)SO₂Me CN COPh 17 NMeSO₂Ph CN COPh 18 N(nPr)SO₂Ph CN COPh 19 COOH Ph COPh 20 COOMe Ph COPh 21 COOEt Ph COPh 22 COO-tBu Ph COPh 23 CONH₂ Ph COPh 24 CONHMe Ph COPh 25 CONHEt Ph COPIi 26 CONH-nPr Ph COPh 27 CONMe₂ Ph COPh 28 CONEt₂ Ph COPh 29 CON(nPr)₂ Ph COPh 30 CONHPh Ph COPh 31

Ph COPh 32

Ph COPh 33

Ph COPh 34 NH₂ Ph COPh 35 NHMe Ph COPh 36 NHEt Ph COPh

TABLE 22 Compd No R⁴ R⁷ R⁸ 1 NH-nPr Ph COPh 2 NMe₂ Ph COPh 3 NEt₂ Ph COPh 4 N(nPr)₂ Ph COPh 5

Ph COPh 6

Ph COPh 7

Ph COPh 8 NHCOMe Ph COPh 9 NHCOEt Ph COPh 10 NHCO-nPr Ph COPh 11 NHCOPh Ph COPh 12 NMeCOMe Ph COPh 13 N(nPr)COMe Ph COPh 14 NMeCOPh Ph COPh 15 N(nPr)COPh Ph COPh 16 NHCOOMe Ph COPh 17 NHCOOEt Ph COPh 18 NHCOO-tBu Ph COPh 19 NHCOOCH₂Ph Ph COPh 20 NMeCOOMe Ph COPh 21 N(nPr)COOMe Ph COPh 22 NMeCOOCH₂Ph Ph COPh 23 N(nPr)COOCH₂Ph Ph COPh 24 NHSO₂Me Ph COPh 25 NHSO₂Et Ph COPh 26 NHSO₂Ph Ph COPh 27 NHTs Ph COPh 28 NMeSO₂Me Ph COPh 29 N(nPr)SO₂Me Ph COPh 30 NMeSO₂Ph Ph COPh 31 N(nPr)SO₂Ph Ph COPh 32 COOH H SO₂Ph 33 COOMe H SO₂Ph 34 COOEt H SO₂Ph 35 COO-tBu H SO₂Ph 36 CONH₂ H SO₂Ph 37 CONHMe H SO₂Ph

TABLE 23 Compd No R⁴ R⁷ R⁸ 1 CONHEt H SO₂Ph 2 CONH-nPr H SO₂Ph 3 CONMe₂ H SO₂Ph 4 CONEt₂ H SO₂Ph 5 CON(nPr)₂ H SO₂Ph 6 CONHPh H SO₂Ph 7

H SO₂Ph 8

H SO₂Ph 9

H SO₂Ph 10 NH₂ H SO₂Ph 11 NHMe H SO₂Ph 12 NHEt H SO₂Ph 13 NH-nPr H SO₂Ph 14 NMe₂ H SO₂Ph 15 NEt₂ H SO₂Ph 16 N(nPr)₂ H SO₂Ph 17

H SO₂Ph 18

H SO₂Ph 19

H SO₂Ph 20 NHCOMe H SO₂Ph 21 NHCOEt H SO₂Ph 22 NHCO-nPr H SO₂Ph 23 NHCOPh H SO₂Ph 24 NMeCOMe H SO₂Ph 25 N(nPr)COMe H SO₂Ph 26 NMeCOPh H SO₂Ph 27 N(nPr)COPh H SO₂Ph 28 NHCOOMe H SO₂Ph 29 NHCOOEt H SO₂Ph 30 NHCOO-tBu H SO₂Ph 31 NHCOOCH₂Ph H SO₂Ph 32 NMeCOOMe H SO₂Ph 33 N(nPr)COOMe H SO₂Ph 34 NMeCOOCH₂Ph H SO₂Ph 35 N(nPr)COOCH₂Ph H SO₂Ph 36 NHSO₂Me H SO₂Ph 37 NHSO₂Et H SO₂Ph

TABLE 24 Compd No R⁴ R⁷ R⁸ 1 NHSO₂Ph H SO₂Ph 2 NHTs H SO₂Ph 3 NMeSO₂Me H SO₂Ph 4 N(nPr)SO₂Me H SO₂Ph 5 NMeSO₂Ph H SO₂Ph 6 N(nPr)SO₂Ph H SO₂Ph 7 COOH Me SO₂Ph 8 COOMe Me SO₂Ph 9 COOEt Et SO₂Ph 10 COO-tBu nPr SO₂Ph 11 CONH₂ Me SO₂Ph 12 CONHMe Me SO₂Ph 13 CONHEt Et SO₂Ph 14 CONH-nPr nPr SO₂Ph 15 CONMe₂ Me SO₂Ph 16 CONEt₂ Me SO₂Ph 17 CON(nPr)₂ Me SO₂Ph 18 CONHPh Et SO₂Ph 19

Et SO₂Ph 20

Et SO₂Ph 21

nPr SO₂Ph 22 NH₂ nPr SO₂Ph 23 NHMe nPr SO₂Ph 24 NHEt Et SO₂Ph 25 NH-nPr Me SO₂Ph 26 NMe₂ nPr SO₂Ph 27 NEt₂ Et SO₂Ph 28 N(nPr)₂ Et SO₂Ph 29

Me SO₂Ph 30

Me SO₂Ph 31

Me SO₂Ph 32 NHCOMe Et SO₂Ph 33 NHCOEt Et SO₂Ph 34 NHCO-nPr Et SO₂Ph 35 NHCOPh Me SO₂Ph 36 NMeCOMe Me SO₂Ph

TABLE 25 Compd No R⁴ R⁷ R⁸ 1 N(nPr)COMe Me SO₂Ph 2 NMeCOPh nPr SO₂Ph 3 N(nPr)COPh nPr SO₂Ph 4 NHCOOMe nPr SO₂Ph 5 NHCOOEt Me SO₂Ph 6 NHCOO-tBu Et SO₂Ph 7 NHCOOCH₂Ph nPr SO₂Ph 8 NMeCOOMe Me SO₂Ph 9 N(nPr)COOMe Et SO₂Ph 10 NMeCOOCH₂Ph nPr SO₂Ph 11 N(nPr)COOCH₂Ph Me SO₂Ph 12 NHSO₂Me Et SO₂Ph 13 NHSO₂Et nPr SO₂Ph 14 NHSO₂Ph Me SO₂Ph 15 NHTs Me SO₂Ph 16 NMeSO₂Me Me SO₂Ph 17 N(nPr)SO₂Me nPr SO₂Ph 18 NMeSO₂Ph nPr SO₂Ph 19 N(nPr)SO₂Ph nPr SO₂Ph 20 COOH Br SO₂Ph 21 COOMe CN SO₂Ph 22 COOEt Br SO₂Ph 23 COO-tBu CN SO₂Ph 24 CONH₂ Br SO₂Ph 25 CONHMe Br SO₂Ph 26 CONHEt Br SO₂Ph 27 CONH-nPr Br SO₂Ph 28 CONMe₂ CN SO₂Ph 29 CONEt₂ CN SO₂Ph 30 CON(nPr)₂ CN SO₂Ph 31 CONHPh Br SO₂Ph 32

Br SO₂Ph 33

Br SO₂Ph 34

CN SO₂Ph 35 NH₂ Br SO₂Ph 36 NHMe CN SO₂Ph

TABLE 26 Compd No R⁴ R⁷ R⁸ 1 NHEt Br SO₂Ph 2 NH-nPr CN SO₂Ph 3 NMe₂ Br SO₂Ph 4 NEt₂ Br SO₂Ph 5 N(nPr)₂ CN SO₂Ph 6

Br SO₂Ph 7

Br SO₂Ph 8

Br SO₂Ph 9 NHCOMe CN SO₂Ph 10 NHCOEt Br SO₂Ph 11 NHCO-nPr CN SO₂Ph 12 NHCOPh Br SO₂Ph 13 NMeCOMe Br SO₂Ph 14 N(nPr)COMe CN SO₂Ph 15 NMeCOPh Br SO₂Ph 16 N(nPr)COPh Br SO₂Ph 17 NHCOOMe CN SO₂Ph 18 NHCOOEt Br SO₂Ph 19 NHCOO-tBu Br SO₂Ph 20 NHCOOCH₂Ph Br SO₂Ph 21 NMeCOOMe CN SO₂Ph 22 N(nPr)COOMe Br SO₂Ph 23 NMeCOOCH₂Ph Br SO₂Ph 24 N(nPr)COOCH₂Ph Br SO₂Ph 25 NHSO₂Me CN SO₂Ph 26 NHSO₂Et Br SO₂Ph 27 NHSO₂Ph Br SO₂Ph 28 NHTs CN SO₂Ph 29 NMeSO₂Me Br SO₂Ph 30 N(nPr)SO₂Me Br SO₂Ph 31 NMeSO₂Ph CN SO₂Ph 32 N(nPr)SO₂Ph Br SO₂Ph 33 COOH Ph SO₂Ph 34 COOMe Ph SO₂Ph 35 COOEt Ph SO₂Ph 36 COO-tBu Ph SO₂Ph 37 CONH₂ Ph SO₂Ph

TABLE 27 Compd No R⁴ R⁷ R⁸ 1 CONHMe Ph SO₂Ph 2 CONHEt Ph SO₂Ph 3 CONH-nPr Ph SO₂Ph 4 CONMe₂ Ph SO₂Ph 5 CONEt₂ Ph SO₂Ph 6 CON(nPr)₂ Ph SO₂Ph 7 CONHPh Ph SO₂Ph 8

Ph SO₂Ph 9

Ph SO₂Ph 10

Ph SO₂Ph 11 NH₂ Ph SO₂Ph 12 NHMe Ph SO₂Ph 13 NHEt Ph SO₂Ph 14 NH-nPr Ph SO₂Ph 15 NMe₂ Ph SO₂Ph 16 NEt₂ Ph SO₂Ph 17 N(nPr)₂ Ph SO₂Ph 18

Ph SO₂Ph 19

Ph SO₂Ph 20

Ph SO₂Ph 21 NHCOMe Ph SO₂Ph 22 NHCOEt Ph SO₂Ph 23 NHCO-nPr Ph SO₂Ph 24 NHCOPh Ph SO₂Ph 25 NMeCOMe Ph SO₂Ph 26 N(nPr)COMe Ph SO₂Ph 27 NMeCOPh Ph SO₂Ph 28 N(nPr)COPh Ph SO₂Ph 29 NHCOOMe Ph SO₂Ph 30 NHCOOEt Ph SO₂Ph 31 NHCOO-tBu Ph SO₂Ph 32 NHCOOCH₂Ph Ph SO₂Ph 33 NMeCOOMe Ph SO₂Ph 34 N(nPr)COOMe Ph SO₂Ph 35 NMeCOOCH₂Ph Ph SO₂Ph 36 N(nPr)COOCH₂Ph Ph SO₂Ph

TABLE 28 Compd No R⁴ R⁷ R⁸ 1 NHSO₂Me Ph SO₂Ph 2 NHSO₂Et Ph SO₂Ph 3 NHSO₂Ph Ph SO₂Ph 4 NHTs Ph SO₂Ph 5 NMeSO₂Me Ph SO₂Ph 6 N(nPr)SO₂Me Ph SO₂Ph 7 NMeSO₂Ph Ph SO₂Ph 8 N(nPr)SO₂Ph Ph SO₂Ph

TABLE 29 (I-b)

Compd No R⁴ R⁶ R⁷ R⁸ 1 COOH H H H 2 COOMe H H H 3 COOEt H H H 4 COO-tBu H H H 5 CONH₂ H H H 6 CONHMe H H H 7 CONHEt H H H 8 CONH-nPr H H H 9 CONMe₂ H H H 10 CONEt₂ H H H 11 CON(nPr)₂ H H H 12 CONHPh H H H 13

H H H 14

H H H 15

H H H 16 NHCOOMe H H H 17 NHCOOEt H H H 18 NHCOO-tBu H H H 19 NHCOOCH₂Ph H H H 20 NMeCOOMe H H H 21 N(nPr)COOMe H H H 22 NMeCOOCH₂Ph H H H 23 N(nPr)COOCH₂Ph H H H 24 COOH H Me H 25 COOMe H Me H 26 COOEt H Et H

TABLE 30 Compd No R⁴ R⁶ R⁷ R⁸ 1 COO-tBu H nPr H 2 CONH₂ H Me H 3 CONHMe H Me H 4 CONHEt H Et H 5 CONH-nPr H nPr H 6 CONMe₂ H Me H 7 CONEt₂ H Me H 8 CON(nPr)₂ H Me H 9 CONHPh H Et H 10

H Et H 11

H Et H 12

H Et H 13 NHCOOMe H nPr H 14 NHCOOEt H nPr H 15 NHCOO-tBu H nPr H 16 NHCOOCH₂Ph H Me H 17 NMeCOOMe H Et H 18 N(nPr)COOMe H nPr H 19 NMeCOOCH₂Ph H Me H 20 N(nPr)COOCH₂Ph H nPr H 21 COOH H Br H 22 COOMe H Br H 23 COOEt H CN H 24 COO-tBu H Br H 25 CONH₂ H Br H 26 CONHMe H CN H 27 CONHEt H Br H 28 CONH-nPr H CN H 29 CONMe₂ H Br H 30 CONEt₂ H Br H 31 CON(nPr)₂ H CN H 32 CONHPh H Br H 33

H Br H 34

H CN H 35

H Br H

TABLE 31 Compd No R⁴ R⁶ R⁷ R⁸ 1 NHCOOMe H Br H 2 NHCOOEt H CN H 3 NHCOO-tBu H Br H 4 NHCOOCH₂Ph H CN H 5 NMeCOOMe H Br H 6 N(nPr)COOMe H CN H 7 NMeCOOCH₂Ph H Br H 8 N(nPr)COOCH₂Ph H CN H 9 COOH H Ph H 10 COOMe H Ph H 11 COOEt H Ph H 12 COO-tBu H Ph H 13 CONH₂ H Ph H 14 CONHMe H Ph H 15 CONHEt H Ph H 16 CONH-nPr H Ph H 17 CONMe₂ H Ph H 18 CONEt₂ H Ph H 19 CON(nPr)₂ H Ph H 20 CONHPh H Ph H 21

H Ph H 22

H Ph H 23

H Ph H 24 NHCOOMe H Ph H 25 NHCOOEt H Ph H 26 NHCOO-tBu H Ph H 27 NHCOOCH₂Ph H Ph H 28 NMeCOOMe H Ph H 29 N(nPr)COOMe H Ph H 30 NMeCOOCH₂Ph H Ph H 31 N(nPr)COOCH₂Ph H Ph H 32 COOH H H Me 33 COOMe H H Me 34 COOEt H H Me 35 COO-tBu H H Me 36 CONH₂ H H Me 37 CONHMe H H Me

TABLE 32 Compd No R⁴ R⁶ R⁷ R⁸ 1 CONHEt H H Me 2 CONH-nPr H H Me 3 CONMe₂ H H Me 4 CONEt₂ H H Me 5 CON(nPr)₂ H H Me 6 CONHPh H H Me 7

H H Me 8

H H Me 9

H H Me 10 NHCOOMe H H Me 11 NHCOOEt H H Me 12 NHCOO-tBu H H Me 13 NHCOOCH₂Ph H H Me 14 NMeCOOMe H H Me 15 N(nPr)COOMe H H Me 16 NMeCOOCH₂Ph H H Me 17 N(nPr)COOCH₂Ph H H Me 18 COOH H Me Me 19 COOMe H Me Me 20 COOEt H Et Me 21 COO-tBu H nPr Me 22 CONH₂ H Me Me 23 CONHMe H Me Me 24 CONHEt H Me Me 25 CONH-nPr H Et Me 26 CONMe₂ H Et Me 27 CONEt₂ H Et Me 28 CON(nPr)₂ H nPr Me 29 CONHPh H nPr Me 30

H nPr Me 31

H Me Me 32

H Et Me 33 NHCOOMe H nPr Me 34 NHCOOEt H Me Me

TABLE 33 Compound No R⁴ R⁶ R⁷ R⁸ 1 NHCOO-tBu H Et Me 2 NHCOOCH₂Ph H nPr Me 3 NMeCOOMe H Me Me 4 N(nPr)COOMe H Me Me 5 NMeCOOCH₂Ph H Et Me 6 N(nPr)COOCH₂Ph H nPr Me 7 COOH H Br Me 8 COOMe H CN Me 9 COOEt H Br Me 10 COO-tBu H CN Me 11 CONH₂ H Br Me 12 CONHMe H CN Me 13 CONHEt H Br Me 14 CONH-nPr H CN Me 15 CONMe₂ H Br Me 16 COONEt₂ H CN Me 17 CON(nPr)₂ H Br Me 18 CONHPh H CN Me 19

H Br Me 20

H Br Me 21

H CN Me 22 NHCOOMe H CN Me 23 NHCOOEt H Br Me 24 NHCOO-tBu H CN Me 25 NHCOOCH₂Ph H Br Me 26 NMeCOOMe H Br Me 27 N(nPr)COOMe H CN Me 28 NMeCOOCH₂Ph H Br Me 29 N(nPr)COOCH₂Ph H Br Me 30 COOH H Ph Me 31 COOMe H Ph Me 32 COOEt H Ph Me 33 COO-tBu H Ph Me 34 CONH₂ H Ph Me 35 CONHMe H Ph Me 36 CONHEt H Ph Me 37 CONH-nPr H Ph Me

TABLE 34 Compd No R⁴ R⁶ R⁷ R⁸ 1 CONMe₂ H Ph Me 2 CONEt₂ H Ph Me 3 CON(nPr)₂ H Ph Me 4 CONHPh H Ph Me 5

H Ph Me 6

H Ph Me 7

H Ph Me 8 NHCOOMe H Ph Me 9 NHCOOEt H Ph Me 10 NHCOO-tBu H Ph Me 11 NHCOOCH₂Ph H Ph Me 12 NMeCOOMe H Ph Me 13 N(nPr)COOMe H Ph Me 14 NMeCOOCH₂Ph H Ph Me 15 N(nPr)COOCH₂Ph H Ph Me 16 COOH H H COPh 17 COOMe H H COPh 18 COOEt H H COPh 19 COO-tBu H H COPh 20 CONH₂ H H COPh 21 CONHMe H H COPh 22 CONHEt H H COPh 23 CONH-nPr H H COPh 24 CONMe₂ H H COPh 25 CONEt₂ H H COPh 26 CON(nPr)₂ H H COPh 27 CONHPh H H COPh 28

H H COPh 29

H H COPh 30

H H COPh 31 NHCOOMe H H COPh 32 NHCOOEt H H COPh 33 NHCOO-tBu H H COPh 34 NHCOOCH₂Ph H H COPh

TABLE 35 Compd No R⁴ R⁶ R⁷ R⁸ 1 NMeCOOMe H H COPh 2 N(nPr)COOMe H H COPh 3 NMeCOOCH₂Ph H H COPh 4 N(nPr)COOCH₂Ph H H COPh 5 COOH H Me COPh 6 COOMe H nPr COPh 7 COOEt H Et COPh 8 COO-tBu H Et COPh 9 CONH₂ H Et COPh 10 CONHMe H Me COPh 11 CONHEt H Me COPh 12 CONH-nPr H Me COPh 13 CONMe₂ H nPr COPh 14 CONEt₂ H nPr COPh 15 CON(nPr)₂ H nPr COPh 16 CONHPh H Me COPh 17

H Et COPh 18

H nPr COPh 19

H Me COPh 20 NHCOOMe H Me COPh 21 NHCOOEt H Me COPh 22 NHCOO-tBu H Et COPh 23 NHCOOCH₂Ph H nPr COPh 24 NMeCOOMe H Et COPh 25 N(nPr)COOMe H nPr COPh 26 NMeCOOCH₂Ph H Me COPh 27 N(nPr)COOCH₂Ph H Me COPh 28 COOH H Br COPh 29 COOMe H CN COPh 30 COOEt H Br COPh 31 COO-tBu H CN COPh 32 CONH₂ H Br COPh 33 CONHMe H Br COPh 34 CONHEt H CN COPh 35 CONH-nPr H CN COPh 36 CONMe₂ H Br COPh

TABLE 36 Compd No R⁴ R⁶ R⁷ R⁸ 1 CONEt₂ H Br COPh 2 CON(nPr)₂ H Br COPh 3 CONHPh H Br COPh 4

H CN COPh 5

H CN COPh 6

H Br COPh 7 NHCOOMe H CN COPh 8 NHCOOEt H Br COPh 9 NHCOO-tBu H CN COPh 10 NHCOOCH₂Ph H Br COPh 11 NMeCOOMe H CN COPh 12 N(nPr)COOMe H Br COPh 13 NMeCOOCH₂Ph H Br COPh 14 N(nPr)COOCH₂Ph H Br COPh 15 COOH H Ph COPh 16 COOMe H Ph COPh 17 COOEt H Ph COPh 18 COO-tBu H Ph COPh 19 CONH₂ H Ph COPh 20 CONHMe H Ph COPh 21 CONHEt H Ph COPh 22 CONH-nPr H Ph COPh 23 CONMe₂ H Ph COPh 24 CONEt₂ H Ph COPh 25 CON(nPr)₂ H Ph COPh 26 CONHPh H Ph COPh 27

H Ph COPh 28

H Ph COPh 29

H Ph COPh 30 NHCOOMe H Ph COPh 31 NHCOOEt H Ph COPh 32 NHCOO-tBu H Ph COPh

TABLE 37 Compd No R⁴ R⁶ R⁷ R⁸ 1 NHCOOCH₂Ph H Ph COPh 2 NMeCOOMe H Ph COPh 3 N(nPr)COOMe H Ph COPh 4 NMeCOOCH₂Ph H Ph COPh 5 N(nPr)COOCH₂Ph H Ph COPh 6 COOH H H SO₂Ph 7 COOMe H H SO₂Ph 8 COOEt H H SO₂Ph 9 COO-tBu H H SO₂Ph 10 CONH₂ H H SO₂Ph 11 CONHMe H H SO₂Ph 12 CONHEt H H SO₂Ph 13 CONH-nPr H H SO₂Ph 14 CONMe₂ H H SO₂Ph 15 CONEt₂ H H SO₂Ph 16 CON(nPr)₂ H H SO₂Ph 17 CONHPh H H SO₂Ph 18

H H SO₂Ph 19

H H SO₂Ph 20

H H SO₂Ph 21 NHCOOMe H H SO₂Ph 22 NHCOOEt H H SO₂Ph 23 NHCOO-tBu H H SO₂Ph 24 NHCOOCH₂Ph H H SO₂Ph 25 NMeCOOMe H H SO₂Ph 26 N(nPr)COOMe H H SO₂Ph 27 NMeCOOCH₂Ph H H SO₂Ph 28 N(nPr)COOCH₂Ph H H SO₂Ph 29 COOH H Me SO₂Ph 30 COOMe H Et SO₂Ph 31 COOEt H nPr SO₂Ph 32 COO-tBu H Et SO₂Ph 33 CONH₂ H nPr SO₂Ph 34 CONHMe H Me SO₂Ph 35 CONHEt H Me SO₂Ph 36 CONH-nPr H nPr SO₂Ph

TABLE 38 Compd No R⁴ R⁶ R⁷ R⁸ 1 CONMe₂ H nPr SO₂Ph 2 CONEt₂ H Et SO₂Ph 3 CON(nPr)₂ H Et SO₂Ph 4 CONHPh H nPr SO₂Ph 5

H nPr SO₂Ph 6

H nPr SO₂Ph 7

H Me SO₂Ph 8 NHCOOMe H Me SO₂Ph 9 NHCOOEt H Me SO₂Ph 10 NHCOO-tBu H Et SO₂Ph 11 NHCOOCH₂Ph H Et SO₂Ph 12 NMeCOOMe H Et SO₂Ph 13 N(nPr)COOMe H Me SO₂Ph 14 NMeCOOCH₂Ph H Me SO₂Ph 15 N(nPr)COOCH₂Ph H Me SO₂Ph 16 COOH H Br SO₂Ph 17 COOMe H Br SO₂Ph 18 COOEt H Br SO₂Ph 19 COO-tBu H CN SO₂Ph 20 CONH₂ H Br SO₂Ph 21 CONHMe H Br SO₂Ph 22 CONHEt H Br SO₂Ph 23 CONH-nPr H CN SO₂Ph 24 CONMe₂ H Br SO₂Ph 25 CONEt₂ H Br SO₂Ph 26 CON(nPr)₂ H Br SO₂Ph 27 CONHPh H CN SO₂Ph 28

H Br SO₂Ph 29

H Br SO₂Ph 30

H Br SO₂Ph 31 NHCOOMe H Br SO₂Ph 32 NHCOOEt H CN SO₂Ph 33 NHCOO-tBu H Br SO₂Ph

TABLE 39 Compd

No R⁴ R⁶ R⁷ R₈ 1 NHCOOCH₂Ph H Br SO₂Ph 2 NMeCOOMe H Br SO₂Ph 3 N(nPr)COOMe H CN SO₂Ph 4 NMeCOOCH₂Ph H Br SO₂Ph 5 N(nPr)COOCH₂Ph H Br SO₂Ph 6 COOH H Ph SO₂Ph 7 COOMe H Ph SO₂Ph 8 COOEt H Ph SO₂Ph 9 COO-tBu H Ph SO₂Ph 10 CONH₂ H Ph SO₂Ph 11 CONHMe H Ph SO₂Ph 12 CONHEt H Ph SO₂Ph 13 CONH-nPr H Ph SO₂Ph 14 CONMe₂ H Ph SO₂Ph 15 CONEt₂ H Ph SO₂Ph 16 CON(nPr)₂ H Ph SO₂Ph 17 CONHPh H Ph SO₂Ph 18

H Ph SO₂Ph 19

H Ph SO₂Ph 20

H Ph SO₂Ph 21 NHCOOMe H Ph SO₂Ph 22 NHCOOEt H Ph SO₂Ph 23 NHCOO-tBu H Ph SO₂Ph 24 NHCOOCH₂Ph H Ph SO₂Ph 25 NMeCOOMe H Ph SO₂Ph 26 N(nPr)COOMe H Ph SO₂Ph 27 NMeCOOCH₂Ph H Ph SO₂Ph 28 N(nPr)COOCH₂Ph H Ph SO₂Ph 29 OH COOMe H H 30 OMe COOMe H H 31 OH COOMe Me H 32 OMe COOMe Me H 33 OH COOMe Br H 34 OMe COOMe Br H 35 OH COOMe Ph H 36 OMe COOMe Ph H 37 OH COOMe H Me 38 OMe COOMe H Me

TABLE 40 Compd No R⁴ R⁶ R⁷ R⁸ 1 OH COOMe Me Me 2 OMe COOMe Et Me 3 OH COOMe Br Me 4 OMe COOMe Br Me 5 OH COOMe Ph Me 6 OMe COOMe Ph Me 7 OH COOMe H COPh 8 OMe COOMe H COPh 9 OH COOMe Me COPh 10 OMe COOMe nPr COPh 11 OH COOMe Br COPh 12 OMe COOMe CN COPh 13 OH COOMe CN COPh 14 OMe COOMe Ph COPh 15 OH COOMe H SO₂Ph 16 OMe COOMe CN SO₂Ph 17 OH COOMe Et SO₂Ph 18 OMe COOMe Me SO₂Ph 19 OH COOMe CN SO₂Ph 20 OMe COOMe Br SO₂Ph 21 OH COOMe Ph SO₂Ph 22 OMe COOMe CN SO₂Ph 23 OH COOEt H H 24 OMe COOEt H H 25 OH COOEt nPr H 26 OMe COOEt Et H 27 OH COOEt Br H 28 OMe COOEt CN H 29 OH COOEt Ph H 30 OMe COOEt CN H 31 OH COOEt H Me 32 OMe COOEt H Me 33 OH COOEt nPr Me 34 OMe COOEt CN Me 35 OH COOEt Br Me 36 OMe COOEt CN Me 37 OH COOEt Ph Me 38 OMe COOEt Ph Me 39 OH COOEt H COPh 40 OMe COOEt CN COPh 41 OH COOEt Me COPh

TABLE 41 Compd No R⁴ R⁶ R⁷ R⁸ 1 OMe COOEt Et COPh 2 OH COOEt Br COPh 3 OMe COOEt CN COPh 4 OH COOEt Ph COPh 5 OMe COOEt CN COPh 6 OH COOEt H SO₂Ph 7 OMe COOEt H SO₂Ph 8 OH COOEt Me SO₂Ph 9 OMe COOEt nPr SO₂Ph 10 OH COOEt CN SO₂Ph 11 OMe COOEt Br SO₂Ph 12 OH COOEt Ph SO₂Ph 13 OMe COOEt Ph SO₂Ph 14 OH CN H H 15 OMe CN CN H 16 OH CN Me H 17 OMe CN Et H 18 OH CN Br H 19 OMe CN CN H 20 OH CN Ph H 21 OMe CN Ph H 22 OH CN H Me 23 OMe CN H Me 24 OH CN CN Me 25 OMe CN Me Me 26 OH CN Br Me 27 OMe CN Br Me 28 OH CN Ph Me 29 OMe CN CN Me 30 OH CN H COPh 31 OMe CN H COPh 32 OH CN CN COPh 33 OMe CN Et COPh 34 OH CN Br COPh 35 OMe CN Br COPh 36 OH CN Ph COPh 37 OMe CN CN COPh 38 OH CN H SO₂Ph 39 OMe CN H SO₂Ph 40 OH CN nPr SO₂Ph 41 OMe CN nPr SO₂Ph

TABLE 42 Compd No R⁴ R⁶ R⁷ R⁸ 1 OH CN Br SO₂Ph 2 OMe CN Br SO₂Ph 3 OH CN CN SO₂Ph 4 OMe CN Ph SO₂Ph 5 OH CH₂NH₂ H H 6 OMe CH₂NH₂ H H 7 OH CH₂NH₂ nPr H 8 OMe CH₂NH₂ Me H 9 OH CH₂NH₂ Br H 10 OMe CH₂NH₂ CN H 11 OH CH₂NH₂ Ph H 12 OMe CH₂NH₂ Ph H 13 OH CH₂NH₂ CN Me 14 OMe CH₂NH₂ H Me 15 OH CH₂NH₂ Et Me 16 OMe CH₂NH₂ CN Me 17 OH CH₂NH₂ Br Me 18 OMe CH₂NH₂ Br Me 19 OH CH₂NH₂ Ph Me 20 OMe CH₂NH₂ CN Me 21 OH CH₂NH₂ H COPh 22 OMe CH₂NH₂ H COPh 23 OH CH₂NH₂ nPr COPh 24 OMe CH₂NH₂ nPr COPh 25 OH CH₂NH₂ Br COPh 26 OMe CH₂NH₂ Br COPh 27 OH CH₂NH₂ Ph COPh 28 OMe CH₂NH₂ Ph COPh 29 OH CH₂NH₂ H SO₂Ph 30 OMe CH₂NH₂ H SO₂Ph 31 OH CH₂NH₂ Me SO₂Ph 32 OMe CH₂NH₂ Me SO₂Ph 33 OH CH₂NH₂ CN SO₂Ph 34 OMe CH₂NH₂ Br SO₂Ph 35 OH CH₂NH₂ CN SO₂Ph 36 OMe CH₂NH₂ Ph SO₂Ph

EXPERIMENTALS

A mixture of radioactive ligands and some cardinal numbers of test compounds was incubated with a sample of cell membrane, which was prepared from brain of rats or HEK293 cells, which expressed the receptor, under the following conditions. Then, the sample was filtered by suction on a Whatman GF/C. Radioactivity on the filter was encountered by the use of a liquid scintillation counter. 50% Inhibitory concentration values (IC₅₀ values) of each selective binding were calculated for test compounds and the Ki value was obtained by applying an equation of Cheng-Prusoff [Biochem. Pharmacol. 22 (1973) 3099-3108] Ki=IC₅₀/(1+[L]/Kd). [L] represents a concentration of the ligand used and Kd shows dissociation constant. TABLE 43 Condition of Receptor Origin Radioactive Ligand Incubation 5-HT1A Rat   1 nM [³H] 8-OH- 25° C.  30 min hippocampus DPAT 5-HT2 Rat cerebral   1 nM [³H] Ketanserin 37° C.  30 min cortex 5-HT6 rat5-HT₆   8 nM [³H] 5HT 25° C. 120 min (HEK293)   4 nM [³H] LSD 37° C.  60 min 5-HT7 Human5-HT₇ 0.5 nM [³H] 5CT 25° C. 120 min (HEK293)

TABLE 44 Ki value (nM) ± SE Example Compd. No 5-HT1A 5-HT6 5-HT7  5 8-1 36 1 2 19-1  81 1 2 19-2  23 97 1 2 19-3  5.7 46 1 2 19-5  10 1 2 19-7  19 1 2 19-10 2.5 1 2 19-15 7.7 4.6 16 1 2 19-16 58 62 86 1 2 19-18 2.7 1 2 19-19 3.8 1 3 20-1  1.7 1 3 20-5  0.49 1 3 20-6  2.7 1 3 20-9  86 78 1 3 20-10 95 45 1 3 20-11 5.7 1 3 20-12 2.7 1 3 20-13 3.9 1 3 20-14 22 1 3 20-15 29 1 3 20-16 22 1 3 20-17 29 1 3 20-18 22 1 3 20-19 12 1 3 20-20 11 1 3 20-21 2.7 1 3 20-22 26 1 3 20-23 9.9 1 3 20-24 3.2 1 3 20-25 36 1 4 21 14 2 4 36-1  29 65 2 4 36-2  8.5 2 4 36-3  58 4.2 2 4 36-4  2 6 38 83 22 2 7 39 27 73 2 8 40 15 32 74 2 9 41 57 3 4 46-2  3 4 46-3  18 3 4 46-1  28 3 5 47 78 3 6 48 1

INDUSTRIAL APPLICABILITY

Having an affinity against serotonin receptors, compounds described in this invention are useful as medicines such as therapeutic agents of diseases for central nervous systems thereof. Furthermore, these compounds are useful as synthetic intermediates thereof. 

1. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof of the formula:

wherein R¹ is hydrogen; R² is hydrogen or lower alkyl; R³ is hydrogen, —COOR¹² (R¹² is hydrogen or ester moiety), or —CN; R⁴ is hydrogen, lower alkyl, —COOR¹³ (R¹³ is hydrogen or ester moiety), —CONR¹⁴R¹⁵ (R¹⁴ and R¹⁵ are each independently hydrogen, lower alkyl, cycloalkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted aryl or optionally substituted heteroaryl, or R¹⁴ and R¹⁵ taken together may form a 5- to 7-membered heterocycle ring with the neighboring nitrogen atom), —CN, —NO₂, —NR¹⁶R¹⁷ (R¹⁶ and R¹⁷ are each independently hydrogen, —CN, optionally substituted lower alkyl, cycloalkyl, cycloalkyl(lower)alkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted amino or R¹⁶ and R¹⁷ taken together may form optionally substituted 5- to 7-membered heterocyclyl with the neighboring nitrogen atom), —NR¹⁸COR¹⁹ (R¹⁸ and R¹⁹ are each independently hydrogen, optionally substituted lower alkyl, cycloalkyl, cycloalkyl(lower)alkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, or optionally substituted heteroaryl), —NR²⁰COOR²¹ (R²⁰ is hydrogen, lower alkyl, cycloalkyl, cycloalkyl(lower)alkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, or optionally substituted heteroaryl; R²¹ is ester moiety), —NR²²SO₂R²³ (R²² is hydrogen, lower alkyl, cycloalkyl, cycloalkyl(lower)alkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, or optionally substituted heteroaryl; R²³ is lower alkyl, cycloalkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted heteroaryl, or lower alkylamino), —OH, lower alkoxy, —SH or lower alkylthio or R³ and R⁴ taken together may form ═O, ═S, or lower alkylene dioxy; R⁵ is hydrogen, or R³ and R⁵ taken together may form a bond; R⁶ is hydrogen, —COOR²⁴ (R²⁴ is hydrogen or ester moiety), —CN, or —CH₂NR²⁵R²⁶ (R²⁵ and R²⁶ are each independently hydrogen, lower alkyl, cycloalkyl, or lower alkenyl); R⁷ is hydrogen, halogen, —CN, optionally substituted lower alkyl, cycloalkyl, cycloalkyl(lower)alkyl, optionally substituted lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted amino, —COOR³⁴ (R³⁴ is hydrogen or ester moiety), —COR³⁵ (R³⁵ is hydrogen, lower alkyl, cycloalkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted amino, optionally substituted aryl, or optionally substituted heteroaryl) or —CHNOH; R⁸ is hydrogen, optionally substituted lower alkyl, cycloalkyl, cycloalkyl(lower)alkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted heteroaryl, —COR²⁷ (R²⁷ is hydrogen, lower alkyl, cycloalkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, or optionally substituted heteroaryl), —COOR²⁸ (R²⁸ is ester moiety), or —SO₂R²⁹ (R²⁹ is lower alkyl, cycloalkyl, optionally substituted lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted heteroaryl), or tri-lower alkyl silyl; R⁹, R¹⁰ and R¹¹ are each independently hydrogen, halogen, optionally substituted lower alkyl, cycloalkyl, cycloalkyl(lower)alkyl, optionally substituted lower alkenyl, lower alkoxy, —OH, —CN, —SR³⁰ (R³⁰ is hydrogen or lower alkyl), —CONH₂, —CHO, —CHNOH, —COOR³¹ (R³¹ is hydrogen or ester moiety), —NR³²R³³ (R³² and R³³ is each independently hydrogen or lower alkyl), optionally substituted aryl or optionally substituted heteroaryl.
 2. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to claim 1, wherein R² is hydrogen.
 3. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to claim 1, wherein R³ is hydrogen.
 4. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to claim 1, wherein R⁵ is hydrogen.
 5. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to claim 1, wherein R³ and R⁵ taken together may form a bond.
 6. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to claim 1, wherein R³ and R⁴ taken together may form ═O, ═S or lower alkylenedioxy.
 7. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to claim 1, wherein R⁴ represents —COOR¹³ (R¹³ is hydrogen or lower alkyl), —NR¹⁶R¹⁷ (R¹⁶ and R¹⁷ are each independently hydrogen, optionally substituted lower alkyl, cycloalkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted amino, or R¹⁶ and R¹⁷ taken together may form an optionally substituted 5- to 7-membered heterocyclyl ring with the neighboring nitrogen atom), —NR¹⁸COR¹⁹ (R¹⁸ and R¹⁹ are each independently hydrogen, optionally substituted lower alkyl or optionally substituted aralkyl), —NR²⁰COOR²¹ (R²⁰ is hydrogen, or lower alkyl; R²¹ is an ester moiety), —NR²²SO₂R²³ (R²² is hydrogen; R²³ is lower alkyl or lower alkylamino), —OH, or lower alkoxy.
 8. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to claim 1, wherein R⁴ is —COOR¹³ (R¹³ is hydrogen or methyl), —NR¹⁶R¹⁷ (R¹⁶ is hydrogen or lower alkyl, R¹⁷ is hydrogen, optionally substituted lower alkyl, cycloalkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted amino or R¹⁶ and R¹⁷ are taken together may form a optionally substituted 5- to 7-membered heterocyclyl ring with the neighboring nitrogen atom), —NR¹⁸COR¹⁹ (R¹⁸ is hydrogen, R¹⁹ is hydrogen, optionally substituted lower alkyl or optionally substituted aralkyl), —NR²⁰COOR²¹ (R²⁰ is hydrogen or methyl; R²¹ is methyl), —NR²²SO₂R²³ (R²² is hydrogen; R²³ is methyl or methylamino), —OH, or lower alkoxy.
 9. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, described in claim 1, wherein R⁴ is —NH₂, —NHCH₃ or N(CH₃)₂.
 10. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, described in claim 1, wherein R⁶ is hydrogen, COOCH₃, COOCH₂CH₃, CN, or CH₂NH₂.
 11. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, described in claim 1, wherein R⁶ is hydrogen.
 12. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, described in claim 1, wherein R⁷ is hydrogen, lower alkyl, halogen, phenyl, —COOR³⁴ (R³⁴ is mentioned before), —CHO or —CHNOH.
 13. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, described in claim 1, wherein R⁷ is hydrogen, methyl, ethyl, halogen, or phenyl.
 14. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to claim 1, wherein R⁸ is hydrogen, optionally substituted lower alkyl, —COR²⁷ (R²⁷ is hydrogen, lower alkyl, cycloalkyl, lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, or optionally substituted heteroaryl), —COOR²⁸ (R²⁸ is ester moiety), or —SO₂R²⁹ (R²⁹ is lower alkyl, cycloalkyl, optionally substituted lower alkenyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted heteroaryl), or tri-lower alkyl silyl.
 15. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to claim 1, wherein R⁸ is hydrogen or —SO₂R²⁹ (R²⁰ is mentioned before).
 16. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to claim 1, wherein all of R⁹, R¹⁰ and R¹¹ are hydrogen.
 17. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to claim 1, wherein R² is hydrogen; R³ and R⁵ are hydrogen or taken together may form a bond.
 18. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to claim 1, wherein R⁶ is hydrogen, COOCH₃, COOCH₂CH₃, CN, or CH₂NH₂; R⁷ is hydrogen, lower alkyl, halogen or phenyl; R⁸ is hydrogen, lower alkyl, COPh, or SO₂Ph (Ph represents phenyl).
 19. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to claim 1, wherein R⁹ is hydrogen or halogen.
 20. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to claim 1, wherein R⁹ is hydrogen.
 21. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, described in to claim 1, wherein R¹⁰ is hydrogen.
 22. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to claim 1, wherein R¹¹ is hydrogen, halogen, lower alkyl, optionally substituted lower alkenyl, —CN, —SR³⁰ (R³⁰ is hydrogen or lower alkyl), —CONH₂, —CHO, —CHNOH, —NR³²R³³ (R³² and R³³ are each independently hydrogen or lower alkyl) or aryl.
 23. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to claim 1, wherein Rid is hydrogen, halogen, methyl, —CN, or —CONH₂.
 24. A compound, prodrug, pharmaceutically acceptable salt or solvate thereof, according to claim 1, wherein R¹, R², R³, R⁵, R⁶, R⁹, and R¹⁰ is hydrogen; R⁴ is —NH₂, —NHCH₃, or —N(CH₃)₂; R⁷ is hydrogen, halogen, lower alkyl, or phenyl; R⁸ is hydrogen or —SO₂R²⁹ (R²⁹ is mentioned before); R¹¹ is hydrogen, halogen, lower alkyl, —CN, or —CONH₂.
 25. A pharmaceutical composition comprising a compound, prodrug, pharmaceutically acceptable salt or solvate thereof according to claim 1, together with a pharmaceutically acceptable additive thereof.
 26. A therapeutic or prophylactic medicament against the serotonin receptors mediated diseases, comprising a compound, prodrug, pharmaceutically acceptable salt or solvate thereof according to claim
 1. 27. A therapeutic or prophylactic medicament according to claim 26, wherein the serotonin receptor is a 5-HT₆ receptor.
 28. A therapeutic or prophylactic medicament according to claim 26, wherein the disease is that of central nervous system.
 29. A therapeutic or prophylactic medicament according to claim 28, wherein the disease of the central nervous system is schizophrenia, Alzheimer's disease, Parkinson's disease, depression, anxiety, pain, or migraine.
 30. A method for treating or preventing a serotonin receptor mediated disease, which comprises administrating to a mammal in need thereof an effective amount of a compound, prodrug, pharmaceutically acceptable salt or solvate thereof according claim
 1. 31. A method for preparing a therapeutic or prophylactic medicament for a serotonin receptor mediated disease, which comprises mixing a compound, prodrug, pharmaceutically acceptable salt or solvate thereof according to claim 1, together with a pharmaceutically acceptable additive thereof. 